- Email: [email protected]
Thiazole-containing compounds as therapeutic targets for cancer therapy
Journal Pre-proof Thiazole-containing compounds as therapeutic targets for cancer therapy Prabodh Chander Sharma, Kushal Kumar Bansal, Archana Sharma, Diksha Sharma, Aakash Deep PII:
S0223-5234(19)31174-2
DOI:
https://doi.org/10.1016/j.ejmech.2019.112016
Reference:
EJMECH 112016
To appear in:
European Journal of Medicinal Chemistry
Received Date: 4 November 2019 Revised Date:
20 December 2019
Accepted Date: 26 December 2019
Please cite this article as: P.C. Sharma, K.K. Bansal, A. Sharma, D. Sharma, A. Deep, Thiazolecontaining compounds as therapeutic targets for cancer therapy, European Journal of Medicinal Chemistry (2020), doi: https://doi.org/10.1016/j.ejmech.2019.112016. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Masson SAS.
Thiazole-containing compounds as therapeutic targets for cancer therapy Prabodh Chander Sharma*a, Kushal Kumar Bansala, Archana Sharmaa, Diksha Sharmaa, Aakash Deepb a
Institute of Pharmaceutical Sciences, Kurukshetra University, Kurukshetra, HR-136119,
India b
Department of Pharmaceutical Sciences, Chaudhary Bansi Lal University, Biwhani-127021,
India Graphical Abstract S
O R2 N
N S
R1 NH
N O
O
CH3
O
O S Cl
N
Cl
Cl
CF3
N S
N
Carbonic Anhy. Inhibitor
N
S N
O S H 2N O
R3
OH
S
N
HO O
O NH HN
N O
S
O
S
N
N
YX
B N
N
A
H2N N
S
S
H3CO
OCH3
OCH3
R
Tubulin Polymerase Inhibitor
NH2
H3CO
Monoacylglycerol lipase Inhibitor
N NH
S
N
N H
CH
Cl
R2
HN N
F N
N
DNA Intercalating Agents
R1
O
S
H N
S N N
S N CH3
S
O
N
N
S
R3
Ar HC N
R1 N N H
N N
N
N N HN
S
R2
H N
S O
Thiazoles as Multi-targeting Agents in Cancer
Cl
Cl
O S N
HO
N
N
NH2
N
NH2
HN
R2 R1
S
F
N H
Cl
Thiazole-containing compounds as therapeutic targets for cancer therapy Prabodh Chander Sharma* a, Kushal Kumar Bansala, Archana Sharmaa, Diksha Sharmaa, Aakash Deepb a
Institute of Pharmaceutical Sciences, Kurukshetra University, Kurukshetra, HR-136119,
India b
Department of Pharmaceutical Sciences, Chaudhary Bansi Lal University, Biwhani-127021,
India Abstract In the last few decades, considerable progress has been made in anticancer agents development, and several new anticancer agents of natural and synthetic origin have been produced. Among heterocyclic compounds, thiazole, a 5-membered unique heterocyclic motif containing sulphur and nitrogen atoms, serves as an essential core scaffold in several medicinally important compounds. Thiazole nucleus is a fundamental part of some clinically applied anticancer drugs, such as dasatinib, dabrafenib, ixabepilone, patellamide A, and epothilone. Recently, thiazole-containing compounds have been successfully developed as possible inhibitors of several biological targets, including enzyme-linked receptor(s) located on the cell membrane, (i.e., polymerase inhibitors) and the cell cycle (i.e., microtubular inhibitors). Moreover, these compounds have been proven to exhibit high effectiveness, potent anticancer activity, and less toxicity. This review presents current research on thiazoles and elucidates their biological importance in anticancer drug discovery. The findings may aid researchers in the rational design of more potent and bio-target specific anticancer drug molecules. Keywords: Heterocycles, 1,3-Thiazoles, Biological targets, Cyclic peptides, Anticancer activity. *Corresponding Author Address: Institute of Pharmaceutical Science, Kurukshetra University, Kurukshetra, HR-136119, India; Contact: +91-94160-25460; E-mail: [email protected]
1
1
Introduction The abnormality in the control mechanism that governs stimulation or suppression in normal cells is the hallmark of cancer [1,2]. The process of carcinogenesis initiates in normal cells as a result of a shift in control mechanism that might be caused due to activation of oncogenes, an inadequate function of tumour suppressor genes and mutagenic factors. The later is also associated with mutations in genes which initiate carcinogenesis. These factors involve distinctive biochemical and oncogenic regulatory pathways (non-enzymatic proteins) [3]. Among oncogenic pathways, RAS and PI3K signaling pathways claimes a higher number of cancers as compared to other pathways. Besides, enzyme malfunctions can cause the accumulation of certain substances that may result in cancer diseases [4,5]. Moreover, cancer may associate to malfunctioning of DNA, RNA, enzymes and some other proteins. Being a carrier of genetic information as well as central to tumour genesis and pathogenesis, DNA is a major target for drug development [6]. Hence, these approaches are being recognized as the potential targets for cancer treatment and drug development. Recent studies revealed that targeted therapy has emerged as a promising approach for the development of selective anticancer agents. Among the different targeted therapies, angiogenesis inhibitors are important classes of drugs which focus on blocking the development of new blood vessels in tumour tissues [7-9]. Target specific anticancer drugs also include DNA intercalators, DNA synthesis inhibitors, transcription regulators, enzyme inhibitors and cancer cell targeting peptides etc. [6]. As per scientific data available, cancer is the second leading cause of death after heart disease in the USA. In 2018, an estimated 1,735,350 new incidences of cancer cases have been diagnosed and 6,09,640 cancer deaths are likely to occurs in the United States, on the top with 14,070 ovarian cancer deaths [10]. The inadequate merits of available anticancer drugs for example lack of selectivity, target specificity, toxicity and developing resistance has led to serious consequences. The radio- and chemotherapeutics are the present methods of treatment of cancer widely known to be characterized by a low therapeutic index [11,12]. Novel approaches targeting the specific molecular alterations that occur in tumour are being used in treatment and eradication of cancers. An ideal anticancer drug would eliminate cancer cells without harming normal tissues. Unfortunately, no currently available agents meet this criterion with a favourable therapeutic index [13]. Therefore, novel anticancer agents owning target specific advanced
2
mechanism of action with favourable therapeutic index are considered valuable in the field of oncology related drug discovery. 2
Thiazole-containing compounds endowed with anticancer activity The biological activity of compounds mainly depends on their molecular structures [14]. Heterocycles, such as azoles occupy a prominent place in current medicinal chemistry due to their wide range of applications in the fields of drug design and discovery [15,16]. Their utility in different areas of medicine, particularly as potential anticancer drugs is being investigated. In recent years, thiazole, a five membered sulphur and nitrogen containing heterocyclic ligand has endorsed considerable interest due to their effective biological properties [17,18]. Thiazole and its derivatives are amongst most active classes of compounds that are known for their broad spectrum of activity e.g. antibacterial activity [19], antifungal activity [20], antimalarial activity [21], antitubercular activity [22], antiviral activity [23], anti-inflammatory activity [24], antidiabetic activity [25], anthelmintic activity [26], anticonvulsant activity [27], antioxidant activity [28], anticancer activity [29] and cardiovascular activity [30], etc. Moreover, thiazole-containing compounds have marked their presence in number of clinically available anticancer drugs (Figure 1) such as, tiazofurin (1) (inhibitor of IMP dehydrogenase) [31], dasatinib (2) (Bcr-Abl tyrosine kinase inhibitor) [32], dabrafenib (3) (inhibitor of enzyme B-RAF) [33], patellamide A (4) (cytotoxicity against multidrug resistant cancer) [34], ixabepilone (5) (stabilization of microtubules) [35], and epothilone (6) (inhibition of microtubule function) [36]. Thiazolecontaining compounds depict anticancer activity profile through diverse mechanisms. Figure 2 presents some of the most potent anticancer compounds bearing thiazole scaffold reported in different scientific studies [37-47]. In view of our continous interest [48-56] in anticancer activity of heterocyclic compounds and thiazole-containing compounds, we have attempted to review various aspects related to anticancer potential of thiazole-containing compounds.
3
5
Tiazofurin - inhibitor of IMP dehydrogenase Dasatinib - Bcr-Abl tyrosine kinase inhibitor Dabrafenib - Inhibitor of enzyme B-Raf
Ixabepilone - stabilization of microtubules Epothilone - inhibition of microtubule function Patellamide A - cytotoxicity against multidrug resistant cancer
S1
4
2
N 3
Thiazole
O
S
HO
N CH3
O
HO
N
N
H N
S
Cl
(1) Tiazofurin
N H
(2) Dasatinib
N
O
N H
N
N
CH3 CH3
HN N
O H N
N O H3C
S
S N
F (3) Dabrafenib
O CH3
S
S
N
(4) Patellamide A
CH3 O
O CH3
O
H3C
NH2
N
H3C
HN
HO H3C O
CH3
N
CH3
O
NH
H3C
N
O S O
H3C
H3C H3C
N
F
H N
OH
H3C H3C O
S
F
N
O
OH
CH3
H3C
CH3
NH2
CH3 CH3 OH
(5) Ixabepilone
O
O
R HO H3C O
CH3
H3C
CH3 OH
(6a,b) Epothilone 6a; (R=H) Epothilone 6b; (R=CH3)
Figure 1: Some clinically used thiazole-cotaining anticancer drugs. The anticancer activity of the compounds through inhibition of various enzymes, miscellaneous targets and cytotoxicity evaluation has been described (Section 2). A brief glimpse on recent patents filed/granted has also been provided (Section 3). Moreover, some selected natural compounds containing thiazole in clinical stage of drug discovery have also been specifically described (Section 4).
4
F
Cl
N
F F
Cl N Cl
S
F
N N N
H N
O
IC50; 5.48-17.80 µM (9)
S
O
O
S
N
O
Anti EGFR IC50; 0.06 µM (10)
HN
Cl HN N
IC50; 0.008-0.025 µM (8)
A2
A3
N
O
NCN
S Anti HAT IC50; 2 µM
S
N
O S
N
O
A1
(11)
IC50; 0.020-0.06 µM
A1, A2, A3 STRUCTURAL MODIFICATIONS
Br
(7) Cl
S N HN
N O
O
NO2 O O
Cl
Key Features
IC50; 8.28-41.48 µM (12)
N S
Cl
S N H
HN N
N S
NH NH IC50; 0.08 µM (14)
N H
IC50; 10.1-25 µM (13)
S
Br
1) Cyanoimine (N-CN) linkage at 4-thiazole showed promising in vitro anticancer activity in compound 7, replacement of cyanoimine (N-CN) linkage with carbonyl (C=O) along with 5-indolyl in compound 8 leads to better profile. 2) Electron withdrawing groups on phenyl ring, such as mono or bi- substituted with F and Cl i.e. compound 9 exhibited significant anticancer activity. 3) Thiazole based pyrazoline derivative (compound 10) possessed promising EGFR kinase inhibitory activity. 4) The existence of thiourea/hydrazine moiety on 2nd position of thiazole seems to exhibit a very good histone acetyl transferase enzyme inhibitory activity in compound 11, and significant cytotoxicity in compounds 13 & 14 5) In case of compound 12, a CONH linkage attached to thiazole nitrogen and para phenyl substitutions with halogen and nitro moieties, respectively demonstrated excellent cytotoxic activities.
Figure 2: Some representatives of thiazole-containing compounds endowed with potent anticancer activities. 2.1 Important enzymatic pathways in carcinogenesis Recently, enzyme inhibition has been identified as an alternative and significant target strategy for the treatment of tumours [57]. Thiazole-containing compounds have been reported effective in inhibiting a number of such enzymes/enzymatic pathways. A number of 5
risk factors lead to the molecular changes or mutations in some important proteins such as tyrosin kinases and initiate the carcinogenesis. These tyrosin kinases serve as important roles in normal cell proliferation, differentiation, cell survival, metabolism, cell migration, cellcycle control through the phosphorylation of tyrosine residues in proteins [58,59]. On the other hand, receptor tyrosine kinases (RTKs) represent high-affinity cell surface receptors that function in transmembrane signalling and play a transforming role in the plethora of cancers [60,61].
Figure 3: Intracelluar signailling pathways activated by tyrosin kinase receptors. Thiazole-containing compounds as small molecular inhibitors (in red lines). Abbreviations; EGF: Epidermal growth factor; EGFR: EGF receptor; CDK: cyclin-dependent kinase; PI3K: phosphatidylinositol 3-kinase; AKT: protein kinases B; RAS: Rat sarcoma subfamily of GTPases; MEK: mitogen-activated protein kinase kinase; mTOR: mammalian target of rapamycin; B-RAF: B-type RAF kinase; VEGF: vascular endothelial growth factor; VEGFR: VEGF receptor; src: v-Src (Rous sarcoma virus) tyrosine kinase; HAT: Histone acetylase; HDAC: histone deacetylases; NF-КB: protein complex (nuclear factor kappa-light-chain-enhancer of activated B cells).
Studies revealed that elevated levels of activated Akt, NF-КB, and HIF-1α in neoplastic cells are associated with an increased risk for cancer development [62]. These molecular pathways are also crucial regulators of the angiogenic process, a rate-limiting step in cancer progression and a rational target for tailoring cancer chemoprevention regimens [63,64]. Numerous drugs have been approved by United States Food and Drug Administration (FDA) for the treatment of cancer caused by activated RTKs [65]. Further, it has also been found that targeted therapy has appreciably improved the survival rate of the cancer patients. Monoclonal antibodies and 6
small-molecular inhibitors have been extensively studied and subjected for clinical trial that targets cancer cells. Interestingly, the small-molecular RTKs inhibitors affect multiple tyrosine kinases [66]. Monoclonal antibodies that bind to the extracellular domain of ErbB2 (trastuzumab/herceptin) or EGFR (cetuximab/erbitux and panitumumab/vectibix) have been successfully used to treat mammary carcinoma, colorectal cancer, and head and neck cancers, respectively. A new thiazole-containing anticancer drug dasatinib (sprycel) targets Abl, Arg, KIT, PDGFR, Src in the treatment of chronic myelogenous leukemia (CML) [67,68] and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). Recent scientific data reveals that thiazole containing compounds have significant potential in interfering and inhibiting the above dicussed enzyme targets as described in (Figure 3). Some important enzymes that play a vital role in cancer progress and intractions/inhibition of these biotargets by thiazole-containing compounds are described in following text. 2.1.1
EGFR kinase inhibitors The epidermal growth factor receptor (EGFR) is an earlier proposed target for cancer treatment. The increase in EGFR expression causes development of aggressive subtype of certain cancers such as triple-negative breast cancer (TNBC) [69]. Thiazoles in conjugation with heterocyclic compounds have been studied for their EGFR kinase inhibitory activity as potential antitumour agents. Recently, thiazolyl-pyrazoline derivatives were scrutinized by Lv et al. in order to explore their potential as EGFR kinase inhibitory activity. Compound (15a) displayed the most potent EGFR TK inhibitory activity with IC50 of 0.06 µM. Molecular docking results indicated that compound (15a) was bound to the EGFR kinase with three hydrogen bonds. Furthermore, this compound also displayed significant in vitro antiproliferative activity against MCF-7 with IC50 of 0.07 µM, which was comparable to standard drug erlotinib (IC50; 0.02 µM). All the test compounds (15a–15f) displayed good antiproliferative activity against MCF-7 with IC50 ranging from 0.16 to 1.47 µM. Hence, compound (15a) might be considered as valuable candidate for further chemical modifications [44]. Wang et al. evaluated novel thiazolyl-pyrazoline clubbed benzodioxole derivatives for their in vitro antiproliferative activity against HER-2 (EGFR family), MCF-7 (human breast cancer cell lines) and B16-F10 cells (mouse melanoma cell lines). Generally, the test compounds revealed good inhibition against both the cell lines MCF-7 and B16-F10 with IC50 values between 0.09 and 4.53 µM, 0.12 and 4.43 µM, respectively. From the series, compound (16) 7
bearing one bromine atom at para- position on phenyl ring exhibited the most potent inhibitory activity against HER-2 (EGFR family), MCF-7 (human breast cancer cell lines) and B16-F10 cells (mouse melanoma cell lines) with IC50; 0.18 µM for HER-2, IC50; 0.09 and 0.12 µM, respectively in comparison to the positive control erlotinib (IC50; 0.02-0.05 µM) [70]. Cytotoxic
activity
of
some
novel
N-pyridinyl-2-(6-phenylimidazo[2,1-b]thiazol-3-
yl)acetamide against two (HEPG2, MDA-MB-231) human cancer cell lines and inhibitory activity against VEGFR2 kinase was carried out by Ding et al. Results indicated that among the test compounds, compound (17) have showed VEGFR2 kinase inhibition at a rate of 5.72% (20 µM) and was a potent inhibitor against MDA-MB-231 (IC50; 1.4 µM), HEPG2 cell line (IC50; 22.6 µM) as compared to standard drug sorafenib (IC50; 5.2 µM). However, one compound (18) showed only 3.76% rate of inhibition on VEGFR2 kinase and exhibited reasonable cytotoxic activity against the HEPG2 and MDA-MB-231 cell lines which provides a potential hit lead for further investigation to be used as cytotoxic agent [71]. In another study, Lv et al. introduced two series of thiazolidinone derivatives and assayed for inhibitory action against EGFR and HER-2 kinases. Some of the synthesized compounds displayed potent EGFR and HER-2 inhibitory activities. Compound (19) displayed the most potent EGFR and HER-2 inhibitory activities (IC50; 0.09 µM for EGFR and IC50; 0.42 µM for HER-2) in MCF-7 cell lines as compared to erlotinib. The EGFR molecular docking model suggested that compound (19) have shown excellent binding on the hydroxyl group, also formed hydrogen bond projected towards the mercapto group of Met 769, side chain mercapto group of Cys 751, respectively [72]. Bhanushali et al. screened a novel series of 5-benzylidene-2,4-thiazolidinediones and evaluated in vitro VEGFR-2 kinase inhibitors in order to find out anti-angiogenesis activity. Compounds (20) and (21) demonstrated prominent inhibitory activity in CAM and zebrafish assay; and were selected for the VEGFR kinase inhibition. Further, only compound (21) was found to inhibit the kinase at IC50 of 0.5 µM, while compound (20) did not show any noteworthy inhibitory activity at tested concentrations [73].
8
R2
N N
O
Active compound 15a; R2; 4-F IC50; 0.06 µM
R1
N
O
Br
N N
S (15) Compd.
R1
15a; 15b; 15c; 15d; 15e; 15f;
3,4-diCH3 3,4-diCH3 3,4-diCH3 3,4-diCH3 3,4-diCH3 3,4-diCH3
R3 R2
N Br
S
Active compound 15a; R3; 4-Cl
(16)
R3
4-F 4-Cl 4-Br 4-CH3 4-OCH3 4-OH
4-Cl 4-Cl 4-Cl 4-Cl 4-Cl 4-Cl
O N
NH
N
N
Cl N N
S (17)
H3C O
O O
N
HO
S
N NH
O
N S
N
N
N H
N
Br
(19)
(18) O
O
O
(20)
N
O S HN
S
HN
HN
S
HN
O
O
O
N O
(21)
Figure 4: Thiazole derivatives as EGFR/VGFER kinase inhibitors (15-21). 2.1.2
Akt (PKB) protein kinases inhibitors Akt (PKB) protein kinases have been appeared as critical mediator of human physiology that controls an impressive array of diverse cellular functions, including the modulation of growth, survival, proliferation and metabolism. The isoforms of Akt (PKB) protein kinases play important role in the regulation of metabolism and cancers [74,75]. In this context, Chang et al. identified a new series of 2-substituted thiazole carboxamide derivatives as effective pan inhibitors against the isoforms of Akt (Akt1, Akt2 and Akt3) and as cell growth inhibitors against LnCaP, PC3, Du145 cell lines. Among the test compounds, one compound (22) (pyrrolopyridine core) which was found as most potent, inhibited the kinase activities of Akt1, Akt2 and Akt3 with IC50 values of 25, 196 and 24 nM, respectively. Furthermore, the compound was observed as potent inhibitor of phosphorylation of
9
downstream MDM2 and GSK3b proteins, and exhibited strong antiproliferative activity in prostate cancer cells [76]. In another study, Altintop et al. synthesized a new series of thiazole-containing compounds via targeting Akt pathway in cancer cells.
Additionally, cytotoxic studies were also
performed against on human lung adenocarcinoma (A549), rat glioma (C6), and mouse embryonic fibroblast cell lines (NIH/3T3). The in vitro cytotoxic screening revealed that compound (23) was most potent due to its significant inhibitory effects on A549 and C6 cell lines with IC50 values of 12 ± 1.73 µg/ml and 3.83 ± 0.76 µg/ml, respectively as compared to cisplatin (IC50;17.33 ± 2.08, 12.67 ± 3.06 µg/ml). Furthermore, compound (23) exhibited early apoptotic effect with 2.3 %, 4.6% and late apoptotic effect 36.5 %, 28.2 % on A549 and C6 cell lines, respectively. Compound (23) was also found as most potent Akt inhibitor in C6 cell line (71.66 ± 4.09 %), while cisplatin with 77.25 ± 5.75 % inhibition [77].
NH2
HN N
Cl
O S
N H
N
O
S NC
Cl
N
N H
(22)
N
CN
(23)
Figure 5: Thiazole derivatives as Akt (PKB) protein kinases inhibitors (22-23).
2.1.3
ALK/ TGF-β type I receptor kinase inhibitors The TGF-β type I receptor kinase (ALK5) is an attractive target in human tumours as well as in preclinical models of cancer. A number of potent, selective ALK5 inhibitors have been discovered which interact with the ATP-binding site of ALK5 [78]. A series of 5-(pyridin-2-yl)thiazoles were evaluated by Kim et al. for their ALK5 inhibitory activity in cell-based luciferase reporter assays. Amongst them, compounds (24) and (25) showed more than 95% inhibition at 0.1 µM in luciferase reporter assays using HaCaT cells transiently transfected with p3TP-luc reporter construct and ARE-luciferase reporter construct. The results recommended that only selected compounds might be considered as new leads in the development of novel antitumour agents [79].
10
Amada et al. have identified novel 5-(1,3-benzothiazol-6-yl)-4-(4-methyl-1,3-thiazol-2-yl)1H-imidazole derivatives as TGF-β (activin-like kinase 5 or ALK5) inhibitors. Among the test compounds, one compound (26) was found as potent inhibitor of ALK5 and TGF-β at a cellular level with (IC50; 5.5 nM), (IC50; 36 nM), respectively through induction of Smad 2/3 phosphorylation. In addition, topical application of 3% lotion of the compound (26) in mouse skin significantly inhibited Smad 2 phosphorylation i.e. (90% inhibition compared with vehicle-treated animals) [80]. In another study, Amada et al. reported novel 4-thiazolylimidazole derivatives as TGF-β (activin-like kinase 5 or ALK5) inhibitors. One compound namely N-{[5-(1,3-benzothiazol6-yl)-4-(4-methyl-1,3-thiazol-2-yl)-1H-imidazol-2-yl]methyl}butanamide (27), was the most potent elective ALK5 inhibitor with IC50; 8.2 nM. The compound (27) was also found to possess good inhibitory activity against TGF-β-induced Smad2/3 phosphorylation at a cellular level with IC50; 32 nM [81]. N
O O O
N H3C
NH2
N H
S N
O
N
H3C
N
(24)
NH2
N H
S
(25) CH3 N
N HN
N
N OH N S H3C
CH3 (26)
NH
S
O H3C
S
S
N
H N
CH3
N O (27)
Figure 6: Thiazole derivatives as ALK/ TGF-β type I receptor kinase inhibitors (24-27). 2.1.4
Aromatase inhibitors Several synthetic aromatase inhibitors (AIs) have been developed with slightly improved survival outcomes when compared to tamoxifen for the treatment of postmenopausal estrogen receptor-positive breast cancer. Aromatase is a heme-containing enzyme that exhibits its 11
inhibitory effect by blocking the last step in biosynthesis, the conversion of androgens to estrogens. Currently, type-I (steroidal drugs) and type-II (nonsteroidal drugs) are in clinical use [82,83]. Herein, thiazole-containing compounds have been reported as novel aromatase inhibitors. Mayhoub et al. presented a novel 2,4-diaryl-1,3-thiazole scaffold and provided more flexible synthetic pathways to build novel aromatase inhibitors with IC50 values in the nanomolar range. Using the new scaffold and optimizing the position of the hydrogen-bond acceptor on the ‘A’ ring of the lead molecule afforded compound 4-(4-(pyridin-3-yl)thiazol-2-yl)pyridine (28b), which had an aromatase IC50 value of 4 nM. In addition to the potent aromatase inhibitory activity of compound (28b), moderate NF-ҡB inhibitory activity was also observed. The methoxy derivative (28a) provided complete aromatase inhibitory selectivity with potency in the low nanomolar range (IC50; 23 nM). It was concluded that aromatase inhibitory activity was enhanced over 6000-fold by using a 1,3-thiazole as the central ring and modifying the substituents on the ‘A’ ring to target the Met374 residue of aromatase [84]. S Active Compound 28b IC50; 4nM
YX
A
N
B N
Compd. 28a; 28b;
X OCH3 -
Y C N
(28)
Figure 7: Thiazole derivatives as aromatase inhibitors (28).
2.1.5
HAT/HDAC (histone acetyltransferase/ histone deacetyltransferase) inhibitors Histone acetylase/histone deacetylase (HAT/HDAC) inhibitors are the exciting new class of drugs that play important roles in transcriptional regulation and pathogenesis of cancer. Protein lysine acetylation has been known as post-translational addition of an acetyl moiety to the ɛ-amino group of a lysine residue while, the reversible modification is known as Nɛacetylation. The enzymes HAT/HDAC involves in catalysis of acetylation and deacetylation of specific lysine residues in the histone tails and contributes in gene transcription since acetylation is associated with an open chromatin configuration and a permissive gene transcription state. Considerable attention has been focussed in these post-translational changes and their implications for the genesis of cancer. Recently, thiazoles have been identified as novel inhibitors of histone acetylase/histone deacetylase (HAT/HDAC) enzymes in the treatment of cancer [85]. 12
Secci et al. have identified a novel HAT (histone acetyltransferase) inhibitor namely 1-(4-(4chlorophenyl)thiazol-2-yl)-2-(alkyl-2-ylidene)hydrazine (29a-29c). The compounds showed selectivity for histone H3 acetylation and significant inhibition in first in vitro screening which was done against recombinant HAT Gcn5 and p300 at increasing concentrations (0.05, 0.1 and 0.2 µM). Afterward, compound (29a) was assayed for HAT inhibitor activity on human cells, HeLa (as control), neuroblastoma from neuronal tissue and glioblastoma from brain tumour. The structure analysis revealed that the 4-chlorophenyl moiety in the C-4 position of the thiazole nucleus showed better inhibition. Further, the cyclopentane ring modification and/or the aromatization/complication decrease the potency. On the other hand, ring opening and chain shortening showed better biological activity which might be due to limited steric hindrance in this portion of the lead compound (29a) [45]. A new series of structurally novel hydroxamic acid-based histone deacetylase (HDAC) inhibitors having both enzymatic and antiproliferative activity have been synthesized by Anandan et al. The thiazole ring attached to a piperazine spacer, which was capped with a sulfonamide group, was developed. The results revealed that hydroxamic acid derivatives (30a) and (30b) with IC50 values (0.09 and 0.07 nM) potently inhibited HDAC enzymes with the best activity as compared to positive control SAHA (IC50; 0.06 & 0.4 µM), respectively. From SAR viewpoint, it has been found that substituent with electron withdrawing groups adjacent to C=O plays an important role in enhanced activity of compounds (30a) and (30b). Rest of all the test compounds were found less potent [86]. In search of potent HAT inhibitors, Carradori et al. explored several new (thiazol-2yl)hydrazones including some related thiazolidines and pyrimidin-4(3H)-ones against human p300 and pCAF-HAT enzymes. The percentages of p300 inhibitory activities for all the compounds were tested at 100 µM while CPTH6 was used as standard drug. Two compounds (31) and (32), showed the highest p300 inhibition (>60%) than the standard drugs. From SAR viewpoint, the insertion of a thiazol-2-yl or pyrid-2-yl ring at the hydrazone function imparts strong HAT inhibition. On the other hand, among the bicyclic rings, the heteroaromatic (1H)indol-3-yl and 2(2H)-chromenon-3-yl furnished the most potent derivatives (31) and (32) with remarkable apoptosis and cytodifferentiation (formation of specialized cells such as muscle, blood, nerve cells from undifferentiated precursor) [87]. Oanh et al. arranged two series of benzothiazole-containing analogues as histone deacetylase inhibitors for cancer treatment. The compounds were also screened for their cytotoxicity 13
against five cancer cell lines, including SW620, MCF-7, PC3, AsPC-1, and NCIH460. Four compounds (33a-33d) bearing –OCH3 and NO2 groups displayed superior HDAC inhibition at 1 µg/ml, and were the most potent cytotoxic agents with the average IC50 values ranging from 0.81-5.49 µg/ml. It was found that compounds with 6C-spacer between benzothiazole and hydroxamic moieties had stronger HDAC inhibition and were more cytotoxic than the compounds with only 4C-spacer [88]. O O S
Cl Active compound 29a; R1; R2; CH3 Inhibitory Conc.; 0.2 mM Compd. 29a; 29b; 29c; O O
R1
HN N
2
R R1
N R
S
N N
S N
(29)
O NHOH
(30)
R2
Active compound 30a; R; 4-CH3 IC50; 0.09 nM
CH3 CH3 CH3 CH2CH3 CH2CH3 CH2CH3
Compd.
R 4-CH3 3,4-diOCH3
30a; 30b;
CH3 Cl
N HN
N
Active compounds 33c; OCH3 33d; NO2 Inhibitory Conc.; 1µ µg/ml
Cl
S
S N NH N NH
(32)
(31) Compd.
R
33a; 33b; 33c; 33d;
H CH3 OCH3 NO2
H
R N S
O HN
N H (33)
OH
O
Figure 8: Thiazole derivatives as HAT/HDAC inhibitors (29-33). 2.1.6
B-RAF inhibitors Many reports inferred that the B-RAF serine/threonine kinase alterations have been observed in different types of human tumours related to cell growth, survival and differentiation. BRAF gene (V600E) is most common in human cancer due to substitution of a valine for glutamic acid at position 600. Inhibition of B-RAF becomes important in many current human cancer therapeutic approaches. Therefore, Zhao et al. prepared a series of 4,5dihydropyrazole derivatives containing thiazole and thiophene moiety and evaluated as potential inhibitors of V600E mutant B-RAF kinase (B-RAFV600E) enzymes contributing to 14
tumour initiation and maintenance. According to the biological activity data, majority of the compounds showed effective B-RAFV600E inhibitory activity and antiproliferative activity against WM266.4 and MCF-7 cell lines. Compound (34) exhibited the most potent antiproliferative activity (IC50; 0.12 µM) against cell line WM266.4 and 0.16 µM against MCF-7 in comparison to sorafenib. Results showed that compound (34) was bearing the potent bioactivity with (IC50; 0.05 µM) against V600E mutant B-RAF kinase (B-RAFV600E). Furthermore, compound (34) induced remarkable apoptosis of MCF-7 and WM266.4 cells in a dose dependent manner. The results of this study might be helpful with in the search of promising B-RAFV600E inhibitor with potent activity [89]. In an another study, a new series of imidazo[2,1-b]thiazole-containing compounds were inspected by Abdel-Maksoud et al. for their in vitro antiproliferative activities against a panel of 57 human cancer cell lines at NCI. Some compounds exhibited comparable mean % inhibition values at 10 µM to sorafenib. Among ethylene analogs, compound (35) holding para-hydroxyphenyl terminal ring showed superior activity with lowest IC50 value 0.475 µM concentration against MCF-7 than sorafenib (IC50; 2.51 µM). The compound (35) was also equipotent to sorafenib over V600E-B-RAF (IC50; 39 nM), wild-type B-RAF, CRAF (IC50; 19 nM), MEK, and ERK kinases. SAR study revealed that hydrogen bond-forming group, such as the hydroxyl group of compound (35), attributed the potent kinase activity [90]. F
Cl F3C N
NH
N
HN O S O
N
S
N N
S HO (34)
N
N
S
(35)
Figure 9: Thiazole derivatives as B-RAF inhibitors (34-35). 2.1.7
Src and Abl kinase inhibitors c-Src and Bcr-Abl are two cytoplasmatic tyrosine kinases (TKs) associated with the development of tumour. The c-Src proto-oncogene plays a major role in the growth, progression, and metastasis of a plathora of human cancers. Through multiple oncogenic pathways, Src kinase modulates signal transduction in EGFR, Her2/neu, PDGFR, FGFR, and 15
VEGFR. Thus, blocking signalling through the inhibition of the kinase activity of Src will be an effective target for treatment of various types of cancers. Because of the structural homology between Src and Abl, several compounds originally synthesized as Src inhibitors have also been shown to be Abl inhibitors [91]. In an attempt, three novel series of 4-benzothiazole amino quinazolines of dasatinib derivative were described by Cai et al. and screened for their in vitro cytotoxic activity against six human cancer cell lines. These compounds were also screened for their Src and Abl kinase inhibitory activity. Cytotoxicity data indicated that 2, 4, 6-trimethylaniline series (38) with IC50; 3.5-24.5 µmol/ml, revealed noteworthy inhibitory activities against all the cell lines. Among the test compounds, compounds (36), (37) and (38) were found as dual inhibitors against Src/Abl kinase activity with more than 90 % inhibition. Thus, the disclosed structures might be the promising lead compounds to be developed as an substitute for current dasatinib therapy or for Imatinib-resistant patients [92]. Lombardo et al. investigated a series of substituted 2-(aminopyridyl)- and 2-(aminopyrimidinyl)thiazole-5-carboxamides as potential Src/Abl kinase inhibitors with promising antiproliferative activity against hematological and solid tumour cell lines. Out of the screend derivatives, derivative (39) (BMS-354825) was confirmed to be a highly potent, ATP competitive inhibitor of both Src and Bcr-Abl (IC50; <1 nM), with kinase inhibitory values of 16 ± 1.0 pM and 30 ± 22 pM, respectively. Further, compound (39) demonstrated 100-fold significant activity against c-kit and PDGFRβ and was orally active in a K562 xenograft model of chronic myelogenous leukemia at multiple dose levels demonstrating regressions of tumour [93].
16
NH2
NH2
O
O
O S CH3
N
CH3
CH3
O
S CH3
N
N
N
Cl
(36)
O
N
H3C O
S
Cl N
O N
NH CH3
N (37)
NH
O CH3
N
N N
H3C
N
H3C
N
N Cl
CH3
O
N N HO
(38)
N
N
HN
N N H
S
O
(39)
Figure 10: Thiazole derivatives as Src and Abl kinase inhibitors (36-39). 2.1.8
Tubulin polymerization inhibitors Microtubules are known to play a vital role in eukaryotic cell growth, division, motility and intracellular trafficking [94]. The natural functions of microtubules are regulated by their polymerization that occurs by a nucleation-elongation mechanism. In the development of the mitotic agents in the treatment of cancer, microtubules have been identified as the best cancer target. Also, the drugs of this class will continue to be important chemotherapeutic agents in the future as more selective approaches are developed [95,96]. Along with this, we have focused on the successful cancer chemotherapy from thiazole-containing compounds and their usefulness as tubulin polymerase inhibitors. Kryshchyshyn et al. developed some fused thiopyrano[2,3-d]thiazoles and screened them as anticancer agents against 60 tumour cell lines. Anticancer activity evaluation was done via three dose response parameter e.g. growth inhibition of 50% (logGI50) total growth inhibition (logTGI) Lethal concentration (logLC50) with in a concentration range (10-4 to 10-8). Out of test compounds, compound (40) (trifluromethane on phenyl ring) was most potent as cytostatic showing moderate selectivity ratio 3.25 at GI50 values 0.37 and 0.67 µM against leukemia, non-small cell lung cancer, colon cancer, CNS cancer, melanoma, prostate cancer and breast cancer subpanel with logGI50; −6.22, logTGI; −4.82, logLC50; −4.21. Compared analysis of the test compounds suggested that the high sensitivity of compound (40) have 17
some correlation with rhizoxin inhibition of β-tubulin in eukaryotic cells disrupting microtubule formation [97]. A series of cis-restricted combretastatins along with 5-membered heterocycles such as thiazole, pyrazole and triazole have been developed by Ohsumi et al. These analogues were tested for their antitubulin activity, cytotoxic activity against the colon 26 adenocarcinoma cancer cell lines and for antitumour activity colon 26 murine tumour models were used. Some of the tested heterocyclic analogues possessed significant antitubulin and cytotoxic activities. Among the tested thiazole-containing compounds, compound (41) demonstrated in vitro antitubulin activity (IC50; 1 µM), cytotoxicity (IC50; 57.5 nM). Further, compound (41) showed potent antitumour activity with tumour suppression (IR=75%, 40 mg/kg) comparable to that of AC-7739 [98]. Romagnoli et al. have introduced novel 2-substituted-4-(3ʹ,4ʹ,5ʹ-trimethoxyphenyl)-5-aryl thiazole-containing compounds in order to screen for their in vitro anticancer activity against various cell lines viz. HeLa, A549, HL-60, Jurkat, MCF-7 and HT-29. Biological findings revealed that antiproliferative activity is attributed to C-2 position of the thiazole ring. Among the test compounds, the thiazole derivative (42) exhibited most potent antiproliferative activity (GI50 1.7-38 µM) than the standard CA-4 against the tested cancer cell lines. Further compound (42) was found as most active inhibitor of tubulin polymerization (IC50; 0.89 µM) and strongly inhibited the binding of [3H] colchicine to tubulin (83% inhibition) [99]. Synthesis of two novel series of 3,4-diarylthiazol-2(3H)-ones and three 3,4-diarylthiazol2(3H)-imines and assessment for their cytotoxicity against a panel of human cancer cell lines was executed by Liu et al. These compounds were screened against Bel-7402, HEPG2, SMMC-7721, human liver cancer; MCF-7, human breast cancer; SW-1990, human pancreatic cancer; HCT116, human colon cancer; CEM, human leukemia using combretastatin A4 (CA-4), a novel cis-stilbene tubulin-binding agent as standard. Compounds (43a) and (43b) exhibited good cytotoxicity against the non-solid human CEM cell line (IC50; 0.24, 0.12 µM) with respect to CA-4 (IC50; 0.002 µM). While, EC50; 3.89 µM and >250 µM, respectively, was reported against a panel of solid human cancer cell lines. Resultant data suggested that compounds with the B-ring possessing the 3,4,5-trimethoxy system and the A-ring with a 4-methoxy substitution were more potent than the isomeric forms [100]. 18
By applying structure-based drug design techniques various colchicine site binding tubulin inhibitors in which ring B was replaced with pharmacologically active benzothiazole nucleus were designed and synthesized by Rao et al. Antiproliferative activity of these analogues were carried out against human cancer cell lines viz., prostate (DU-145, cervix (HeLa), lung adenocarcinoma (A549), liver (HEPG2) and breast (MCF-7), using colchicine as reference compound. The biological results shown that the bioisosters of 1,2,3-triazoles and 1,2,3,4tetrazoles were most active among all with IC50; 0.048-14.67 µM. Compounds (44) and (45) with a C-3 methyl substitution & C-6 methoxy, fluoro 2-phenylbenzothiazole moiety displayed favourable activity with IC50 value of 0.054 and 0.048 µM against the lung cancer cell line [101]. Antiproliferative activity of N,4-diaryl-1,3-thiazole-2-amines as tubulin inhibitors against (gastric adenocarcinoma SGC-7901 cells, lung adenocarcinoma A549 cells and fibrosarcoma HT-1080 cells was done by Sun et al. Most of the screened compounds exhibited moderate antiproliferative activity in comparison to CA-4 , nocodazole and SMART standard drugs. Out of the test compounds, one compound namely N-(2,4-dimethoxyphenyl)-4-(4methoxyphenyl)-1,3-thiazol-2-amine (46) exhibited the most potent antiproliferative activity, with IC50 values between 0.36 and 0.86 µM in the three cancer cell lines. Compound (46) also inhibited tubulin polymerization potently and disrupted microtubule dynamics in a manner similar to CA-4. Moreover, compound (46) effectively induced SGC-7901 cell cycle arrest at the G2/M phase in both concentration and time-dependent manners [102]. Shaik et al. introduced a series of 2-anilinopyridinyl-benzothiazole schiff bases and evaluated for their anticancer activity as well as cytotoxic activity. Among the test compounds, compound (47) was the most potent antiproliferating agent against A-549, MCF-7 and DU145 cell lines with GI50 values of 17, 12 and 3.8 µM, respectively. However, compound (48) has been emerged as most effective compound from the series by exhibiting a GI50 of 4.3 µM against A549 cell line. Compound (49) with trimethoxy groups on both the moieties was found to be better than E7010 in binding to the colchicine domain of tubulin, in silico. The test compound, (47) showed 37.85 and 66.09% of cell accumulation in G2/M phase at 2.5 and 5 µM concentrations,whereas the reference compound E7010 showed 50.21% cell accumulation in G2/M phase at 5 µM concentration. Thus, compound (47) competes with colchicine in binding to tubulin and causes cell cycle arrest in G2/M phase by inhibiting tubulin polymerization [103].
19
In an another study, Shaik et al. developed a series of imidazo[2,1-b]thiazole linked triazole conjugates and reported their antiproliferative activity against human cancer cell lines namely HeLa (cervical), DU-145 (prostate), A549 (lung), MCF-7 (breast) and HEPG2 (liver). Out of the tested conjugates, conjugates (50) and (51) demonstrated a significant antiproliferative effect against A549 (IC50 values of 0.924 and 0.778 µM) and MCF-7 (IC50 values of 1.737 and 1.013 µM) cell lines, respectively. SAR study revealed that electron-donating substituents like methoxy on the aryl ring enhanced the activity, while electronegative substituents like fluorine and chlorine on this ring suppressed the activity. Furthermore, compounds (50 and 51) significantly induced inhibition of tubulin polymerization and inhibition of binding of colchicines to tubulin by 70.2 and 74.3% (IC50 values of 1.62 and 1.43 µM), respectively as compared to nocodazole (71.0% inhibition, IC50; 1.59 µM) [42]. Combretastatin A-4 (CA-4) analogs of 3-(trimethoxyphenyl)-2(3H)-thiazole thiones were introduced by Banimustafa et al. and reported their cytotoxic activity against three human cancer cell lines namely MCF-7, MDA-MB-231 and T47D. Among the tested analogues, analog (52) with a substitution of 4-methyl showed potent activity against all cell lines with IC50 values 11.8-19.7 µg/mL. Moreover, bioassays results revealed that compound (52) depolymerized tubulin, inhibited cell proliferation, and induced apoptosis in cancer cells. In addition, compound (52) (selectivity index >5) has shown no significant toxicity towards non-tumoural cell line MRC-5 [104]. Synthesis and anticancer activity of 1,2,3-triazolo linked benzo[d]imidazo[2,1-b]thiazolecontaining compounds as tubulin polymerization inhibitors was executed by Shaik et al. Among the tested derivatives, derivatives (53a) and (53b) having halogen substituted on phenyl ring revealed significant cytotoxic activity against the human breast cancer cell line (MCF-7) with IC50 values of 0.60 and 0.78 µM, respectively. The flow cytometric analysis revealed that these conjugates cause cell cycle arrest at G2/M phase. Moreover, molecular docking study disclosed that compounds (53a) and (53b) could interact with the colchicine binding site between α and β subunits of tubulin [105]. Antiproliferative activity of cis-restricted 2-alkylthio-4-(2,3,4-trimethoxyphenyl)-5-arylthiazole analogues of combretastatin A-4 against human cancer cell lines HT-29, MCF-7, AGS, and a normal mouse fibroblastic cell line NIH-3T3 was done by Salehi et al. Compounds (54a) and (54b), containing the 2-(benzylthio) group on thiazole rings, were the most potent (IC50; <20 µM) in all three cancer cell lines. While replacement of 2-(benzylthio) 20
group decreases the activity of the compounds. However one compound (54a) with para chloro substituted on the phenyl ring and the 2-(benzylthio) group had the highest cytotoxic activity against the HT-29 cell line (IC50; 8.9 µM). In addition, some compounds were found to decrease the polymerization activity of the microtubule relative to the control CA-4 at 10 µM. The order of inhibition of tubulin polymerization was CA-4 > 54a > 54b. The compound with the 2-(benzylthio) group on the thiazole ring and the para chloro substituted 5-phenyl ring (54a) was the most potent inhibitor of tubulin polymerization [106]. Guggilapu et al. reported thiazole linked indolyl-3-glyoxylamide derivatives as novel tubulin polymerization inhibitors. All synthesized compounds were also screened for their in vitro cytotoxic activity against DU145 (prostate), PC-3 (prostate), A549 (lung) and HCT-15 (colon) cancer cell lines. Out of the test compounds, compound (55) displayed cytotoxicity of IC50; 93 nM against DU145 cancer cell line. Compound (55) showed anti-tubulin activity with an inhibition percentage of 68.5% in comparison to the podophyllotoxin (78.0%) The results from molecular modelling studies revealed that compound (55) bind at the colchicine binding site of the tubulin and exhibiting a cell cycle arrest at the G2/M phase [107]. Antiproliferative activity of new imidazo[2,1-b]thiazole-benzimidazole derivatives against HeLa (cervical), A549 (lung), MCF-7 (breast) and DU-145 (prostate) along with normal HEK-293 cell line was done by Baig et al. Among synthesized compounds, compound (56) demonstrated significant cytotoxicity against A549 lung cancer cell line (IC50; 1.08 µM) as compared to standard drug nocodazole (IC50; 1.807 µM). The tubulin polymerization assay revealed that compound (56) disrupted microtubule dynamics and induced abnormal spindle structure and centrosome which causes cell cycle arrest at G2/M phase. Furthermore, mitochondrial membrane potential and annexin V-FITC assay suggested that this compound induced cell death by apoptosis in (A549) human lung cancer cells. Docking studies also support the binding modes of compound (56) at the colchicine site of the tubulin to be act as antitubulin agent [108]. Wang et al. synthesized a series of 4,5-diarylthiazole-containing compounds in order to explore their potential as antiproliferative agents as well as microtubules stabilizing ability. Compound (57) with 3,4,5-trimethoxyphenyl group at the C-4 position and 4-ethoxyphenyl group at the C-5 position of 2-amino substituted thiazole was of the most potent with IC50 values of 8.4–26.4 nM against colon (HCT116 cell), liver (SMMC-7221), ovarian (A2780), hepatocellular (HEPG2), and ovarian (SK-OV-3) cancer cell lines, than CA-4 (IC50; 8.3-10 21
nM). Moreover, compound (57) has also been identified as potent tubulin polymerization inhibitor (resistance ratio 0.51-2.24). Tubulin polymerization assay and an EBI competition binding mechanism revealed that (57) could block the progression of cell cycle in the G2/M phase and result in cellular apoptosis in cancer cells similar to colchicines [109].
2.1.9
Topoisomerase inhibitors DNA topoisomerases are ubiquitous enzymes that are required for proper chromosome structure and segregation and play important roles in the topological states of DNA, such as DNA replication, transcription, and recombination. DNA topoisomerases are categorized into four subfamilies IA, IB, IIA and IIB, and each family possess unique mechanistic features [110,111]. These enzymes are also known for maintenance of genome stability by catalyzing the passage of individual DNA strands (topoisomerase I) or double helices (topoisomerase II) through one another. Clinically used drugs like camptothecin targets topoisomerase I (topo I), while doxorubicin and etoposide are typical topoisomerase II (topo II) inhibitors. Hence, topoisomerases are suitable targets for important anticancer drugs. Herein, thiazole derivatives exhibiting promising topoisomerase inhibitory activity are being addressed in this section. In this context, Choi et al. reported solid phase combinatorial synthesis of biologically active benzothiazole-containing compounds and assessed them for topoisomerase II inhibitory activity. Generally, all the screened derivatives demonstrated good inhibition of topoisomerase II enzyme at 100 µM. One compound 2-(3-amino-4-methylphenyl) benzothiazole (58) displayed potent topoisomerase II inhibitory activity at IC50; 71.7 µM, comparable to etoposide (IC50; 78.4 µM) [112].
22
H
S
O
H2N
H N
N
S
N
O
H S
O F
F F
(40)
NH2
O H3C H3C O
O
H3C H3C
A O
O CH3
S
O
H3C
O
N
A
B O
O O
Compd.
R
43a; 43b;
H Cl
AC-7739
O O O
CH3 CH3
CH3
N
(42)
H3C
O
S
N N N
O
N O
S (45)
F
CH3
H3C
N
O S
O O CH CH3 3
N
N N
S
OCH3 N
NH
S N
N
N NH
O O (51)
N
N N
N N
(50)
S
N
OH CH3 O
O
OCH3
O
H3C
H N
OCH3
Cl
OCH3
N
NH
H3CO
OCH3
F
OCH3
(49) (48)
S
OCH3
N N
S
OCH3
(47)
OCH3
OCH3
N
NH
O CH3
(46)
OCH3 N
N
NH
CH3
O O CH CH3 3
(44) H3C O
CH3
N N N
CH3
O
(43)
CH3
N
S
CH3
CH3
NH2 O
NH
H2N
CH3
O H3C
(41) R
B
O
O CH 3 CH3 O
CH3 O
CH3 O CH3 O
S
N S
CH3 (52)
Figure 11: Thiazole derivatives as tubulin polymerase inhibitors (40-52).
23
O
R N
N
N H
N
S N
N
S
F
H3C
(53) Compd. 53a; 53b;
O
O O
R H CH3
Compd.
R
54a; 54b;
Cl F
CH3
CH3 (54)
NH2
H3C O
O
H3C H3C
O NH
F
N O
S N
(55)
F
H N
N
F N
HN O
S
N
R
CH3 (56)
N
S
O
N
O
H3C
O O
S (57)
CH3
Figure 11 (cont.): Thiazole derivatives as tubulin polymerase inhibitors (53-57). 2-Aminothiazolyl quinolones were synthesized and screened for their antimicrobial and anticancer potential by Cheng et al. To our interest, in vitro cytotoxicity of the synthesized compounds was carried out against L929 (normal mouse fibroblast) cells. The results revealed that compound (59) exhibited lowest toxicity against L929 cells at IC50 value of 289 µg/mL. Further, docking results showed that compound (59) was able to bind with topoisomerase IV-DNA through hydrogen bonds between molecule and residue Arg418 of topoisomerase IV as well as through π-π stacking between molecule and base DA16 of DNA [113]. Beauchard et al. produced a set of novel thiazoloindolo[3,2-c]quinoline, 8-substituted-1Hindolo[3,2-c]quinolone derivatives and evaluated for DNA interaction, topoisomerases inhibition and cytotoxicity against (human leukemia cells) HL60 and HL60/MX2. Most of the synthesized derivatives exhibited interesting in vitro cytotoxic activity against MCF-7 and MDA-MB-231 tumour cells at concentration of 10 µM. Compounds bearing imidazoline cationic side chain on the thiazole ring (60-62) exhibited stronger cytotoxicity. The linear aminothiazoloindolo[3,2-c]quinoline derivative which acts as a DNA-intercalating agent, also displays a significant anti-proliferative activity [114].
24
N
CH
NH2
F
N
N
CH3 S
S
F
(58)
O CH3
N N
NH2
S
N
(60)
(59)
N
N N N N
H N S
N N N
H N
S N N
N N
NH
N
N N (62)
(61)
Figure 12: Thiazole derivatives as topoisomerase IV inhibitors (58-62). 2.1.10 CDC7 inhibitors The Cell division cycle 7 (CDC7) protein kinase is essential for DNA replication and maintenance of genome stability. Given its essential function in cell proliferation, Cdc7 has been considered as a novel target for cancer therapy. Herein, Reichelt et al. have identified trisubstituted thiazoles as CDC7 kinase inhibitors in cancer treatment. These thiazole based compounds were closely related kinase that shares both structural and functional homology with CDC7 kinase. Compound (63) having ester on 5th position and hydroxyl on 4th position of the thiazole was the most promising hit in a series of thiazoles for CDC7 kinase activity with IC50 of 0.323 µM, and no activity at IC50; >125 µM against CDK2. Further amide (64) having 2,4-diCl substitution on phenyl ring was the most potent CDC7 inhibitor with an IC50; 0.00377±0.0016 µM [115].
Cl
Cl N
H2N
OH
N
N O
S
CH3
N
N
O (63)
NH2
S (64)
O
Figure 13: Thiazole derivatives as CDC7 inhibitors (63-64). 2.1.11 Monoacylglycerol lipase (MAGL) inhibitors 25
Human monoacylglycerol lipase (MAGL) is a serine hydrolase enzyme that belongs to the super family of α/β-hydrolases. It has been reported that MAGL regulates a fatty acid network in cancer and is highly aggravated in aggressive cancer cells, including melanoma, breast cancer, ovarian cancer, colorectal carcinoma, and prostate cancer. The cancer promoting activity is due to an elevated free fatty acids (FFA) level, which suggested a new metabolic function of this enzyme. Hence, Afzal et al. reported new N-[4-(1,3-benzothiazol2-yl)phenyl]acetamide derivatives as novel inhibitors of human MAGL enzyme. Compound (65a) was found to be most active with IC50 value of 6.5 nM. In addition to MAGL enzyme assay, in vitro anticancer activity was also performed against NCI-60 cancer cell lines. Overall, one dose assay results showed that majority of the compounds were active against MCF7 and MDA-MB-468 breast cancer cell lines. Out of the test compounds, compounds (65b) and (65c) showed potent anticancer activity at GI50 values for MCF-7 (32.5, 37.1 nM), against MDA-MB-468 (23.8, 25.1 nM), respectively as comparedto 5-FU [116].
R N
Compd. NH
S N H
O
65a; 65b; 65c;
R 3-Cl, 4-F 4-Cl 2,6-Cl2
(65)
Figure 14: Thiazole derivatives as monoacylglycerol lipase (MAGL) inhibitors (65). 2.1.12 Na+/K+-ATPase inhibitors Several types of cancers, especially glioblastomas, melanomas and NSCLCs are associated with dismal prognoses involve the inhibition of various types of ion channels, particularly the alpha-1 subunit of the Na+/K+-ATPase (NAK). These cancers are also resistant to conventional radiotherapy and chemotherapy. Impairing NAK alpha-1 activity represents an efficient approach to killing MDR cancer cells. In this context, Lefranc et al. assessed 26 thiazoles (including 4-halogeno-2,5-disubtituted-1,3-thiazoles) and 5-thienothiazoles for their in vitro anticancer activity against a panel of 6 human cancer cell lines, including glioma cell lines. Compounds (66a) and (66b) displayed ~10 times greater in vitro anti-NAK activity at 1 mM (bioselectivity indices > 5) than perillyl alcohol (POH). Further, compounds (66a) and (66b) displayed inhibitory activity > 50% at 1 mM on purified guinea pig brain NAK, whereas only compound (66b) displayed inhibitory activity > 50% at 1 mM on purified 26
guinea pig kidney NAK. The kinetic study results revealed that compound (66b) interacts by non-competitive inhibition with both Na+/K+ ions [117].
N N
R
S O
Compd.
R
66a; 66b;
Cl Br
(66)
Figure 15: Thiazole derivatives as Na+/K+-ATPase inhibitors (66). 2.1.13 Carbonic anhydrase inhibitors Carbonic anhydrases (CAs) are metalloenzymes which catalyze this reversible hydration reaction of carbon dioxide to bicarbonate and protons (CO2 + H2O
HCO3-+ H+). They
play an important role in tumourigenicity and many other physiological or pathological processes. Sixteen different CA isoforms are known, which vary in localization and tissue distribution, being cytosolic (I, II, III, VII, and XIII), membrane bound (IV, IX, XII, and XIV), mitochondrial (VA and VB) and secreted (VI) forms. The membrane bound CA IX and XII isoforms are known as the CAs associated with cancers, being expressed in a limited number of normal tissues. Solid tumours generally characterized by elevated acidic pH and low level of oxygen (hypoxia) and leads to overexpression of CA IX and CA XII. CA IX also plays a role in providing bicarbonate to be used as a substrate for cell growth, whilst it is established that bicarbonate is required in the synthesis of pyrimidine nucleotides. Motivated by the above findings, Ibrahim et al. reported synthesis and carbonic anhydrase inhibitory properties of benzothiazole-6-sulfonamides. Most of the novel compounds were highly potent inhibitors of the tumour-associated hCA IX and hCA XII with KIs in the nanomolar range 3.5 to 45.4 nM. Among the test compounds, compounds (67) & (68) were found as most potent inhibitors against the slow cytosolic isoform hCA I with KIs in the range of 2.6-12.0 nM. The rest of compounds were found to have moderate activities against hCA I [118]. Suthar et al. have designed novel 4-(4-oxo-2-arylthiazolidin-3-yl)benzenesulfonamide derivatives and checked for their in vitro anticancer as well as selective carbonic anhydrase IX (CA IX) inhibitory activity. The resultant data suggested that compound (69) was found to be the most potent and selective inhibitor of CA IX with inhibitory constant (KI) value of 2.2 nM (selectivity ratio 381 against CA I). In addition, compound (69) showed IC50 values of 5.03 µg/ml (cisplatin: 6.56 µg/ml), 5.81 µg/ml (cisplatin: 5.85 µg/ml), and 23.93 µg/ml (cisplatin: 2.75 µg/ml) against COLO-205, MDA-MB-231, and DU-145 cell lines, 27
respectively. Anticancer activity results showed that compound (69) caused cell shrinkage, nuclear condensation, and nuclear fragmentation events that are characteristic to apoptosis of COLO-205 cells [119]. O O H2N S O
N S
O N H
N
N N
O
O S H2N O
NH
N
Cl (69)
(67)
N
N
N
O
S
O O S H2N O
S
S HN
NH
S
NH2 O
N
S (68)
Figure 16: Thiazole derivatives as carbonic anhydrase inhibitors (67-69). 2.1.14 Sphingosine kinase inhibitors Sphingosine kinases (SphK1, SphK2) are regulators of sphingosine-1-phosphate (S1P) that play an essential role in membrane formation and act as modulators in cell signaling processes. Sph is phosphorylated by SphK to form S1P. SphK exists in two isoforms, SphK1 and SphK2, which differ in their substrate preferences, subcellular localizations and tissue distributions, suggesting that they perform different physiological roles. Sphingosine kinase (SphK) inhibitors are another therapeutic option for treatment of cancer and inflammatory diseases that can promote cell apoptosis and modulate autoimmune diseases. Thus, Vogt et al. have reported 2-aminothiazole-containing compounds as sphingosine kinase inhibitors. From this series, compound (70), ST-1803 exhibited 59.4 ± 3.3% inhibition of SphK1 and 50.0 ± 9.9% inhibition of SphK2 at 10 µM demonstrating the most potent sphingosine kinase inhibitor. An extensive screening of tri-thiazole compound, N-(4-methylthiazol-2-yl)-(2,4’bithiazol)-2’-amine (70), ST-1803 against both the isoenzymes demonstrated IC50 values of 7.3 µM (SphK1), 6.5 µM (SphK2) as a promising candidate for further in vivo studies [120]. H N
S N N
S N CH3
S (70)
28
Figure 17: Thiazole derivative as sphingosine kinase inhibitors (70). 2.1.15 IMP dehydrogenase inhibitors Nucleotide coenzymes have significant role in cellular metabolic processes such as nicotinamide adenine dinucleotide (NAD) in the case of dehydrogenases. Altered NAD metabolism has been observed in many cancers. These dinucleotides are potent inhibitors of inosine 5’-monophosphate dehydrogenase (IMPDH), a rate-limiting enzyme of de novo guanine nucleotides biosynthesis. Thus, thiazole-4-carboxamide adenine dinucleotide (TAD) analogues T-2’-MeAD and T-3’-MeAD containing, respectively, a methyl group at the ribose 2’-C-, and 3’-C-position of the adenosine moiety, were introduced by Franchetti et al. as potent selective human inosine monophosphate dehydrogenase (IMPDH) type II inhibitors. Biological evaluation of dinucleotide (71b) inhibitor of recombinant human IMPDH type I and type II resulted in a good inhibitory activity (0.52 & 0.66 µM, respectively). Inhibition of both isoenzymes by compound (71a) (T-2’-MeAD) and (71b) (T-3’-MeAD) was noncompetitive with respect to NAD substrate. Binding of T-3’-MeAD was comparable to the parent compound TAD, while T-2’-MeAD proved to be a mild inhibitor. On the other hand, no significant variation was found in inhibition of the IMPDH isoenzymes. Compounds (71a) and (71b) were found to inhibit the growth of K562 cells at IC50; 30.7 and 65.0 µM, respectively than tiazofurin (IC50; 4.5 µM) [121]. Active Compound 71b; Inhibitory Conc.; 0.52 & 0.66 µM
NH2 N N N
N
R
CONH2 S
R1
O O O P O P OH OH (71)
O
N Compd.
R
R1
71a; 71b;
CH3 H
H CH3
OH OH
Figure 18: Thiazole derivatives as IMP dehydrogenase inhibitors (71).
2.1.16 Pin1 inhibitor Pin1 (Protein interacting with NIMA1) is a peptidyl prolyl cis–trans isomerase (PPIase) which catalyse the isomerization of the amide bond of pSer/Thr-Pro in its target proteins and is a novel promising anticancer target. A number of structurally distinct small-molecule 29
inhibitors of Pin1 have been reported recently. In this context, Zhao et al. reported a series of new thiazole-containing compounds and assessed their inhibitory activities against human Pin1 using a protease-coupled enzyme assay. All the monosubstituted derivatives exhibited potent Pin1 inhibitory activity within IC50 range of 2.93-51.1 µM. Among them, compound (72) oxoacetic acid was the most potent with IC50; 2.93 µM. The results suggested that an oxalic acid and thiazole ring moiety might be suitable in developing potent Pin1 inhibitors in cancer treatment [122]. HO O
O NH HN
N O
S
O (72)
Figure 19: Thiazole derivatives as Pin1 inhibitor (72). 2.1.17 USP7 inhibitors Herpesvirus-associated Ubiquitin-Specific Protease (USP7, represents the oncogenic protein) interacts with Mdm2 and stabilizes it. USP7 has been identifies as a potential drug target for cancer therapy. USP7 inhibitors have been recently shown to suppress in vitro and in vivo tumour cell growth. In this context, Chen et al. have executed the synthesis and anticancer screening of a series of thiazole-containing compounds against cancer cell lines as well as USP7 enzyme inhibitors. Generally, the test compounds exhibited their effect by inducing cell death in a p53-dependent and p53-independent manner. Compounds (73a-73b) were found as most potent compounds with micromolar concentration given in the table 1. The molecular docking studies revealed that that P22077 (reference compound) and (73a) might bind to the ubiquitin binding pocket to competitively inhibit the binding of ubiquitin to USP7 [123]. Table 1 Thiazole-containing compounds (73a-73b) as USP7 inhibitors (IC50; µM); Compnd.
HCT116 (p53wt/wt)
RMPI-8226 (p53mt/mt)
H1299 (lack of p53 gene)
73a
8.45 ± 1.76
10.97 ± 0.73
6.21 ± 3.28
73b
6.36 ± 2.14
6.11 ± 0.51
3.68 ± 1.10
30
N
O2N
R Compd.
R
S S
Cl
73a;
-COCH3
Cl N
73b;
O
C
N H
F
(73)
Figure 20: Thiazole derivatives as USP7 inhibitors (73). 2.2
Thiazole-containing compounds endowed with anticancer activity: Other modes of action Several key signaling pathways-including PI3K/AKT/mTOR, RAS/MEK/ERK, and p53have been implicated in the tumourigenesis [124]. In the age of small molecule for targeted therapies, thiazole and their derivatives are the emerging class of anticancer which exhibited potential activity against various kinases as well as signalling pathways. In this review, we have also emphasized on some other modes of actions of thiazole-containing compounds besides their action as enzyme inhibitors. Some other modes of actions have been described as: mTOR inhibitors, antifibrotic agents, DNA intercalating agents, apoptotic/angiogenesis inhibitors, NF-kB inhibitors and RSK2 inhibitors.
2.2.1
Thiazole-containing compounds as antifibrotic agents Fibroblasts play a pivotal role in the normal wound healing or tissue repair process and are are associated with cancer cells and cancer progression. Fibroblasts are associated with an array of cytokines targeting the so-called cancer-associated fibroblast (promoters of tumour growth and progression) which is a novel and promising therapeutic strategy against cancer. In this context, a series of 2-amino(imino)-4-thiazolidinone derivatives and 4-Raminothiazol-2(5H)-ones was screened for its antifibrotic and anticancer activities by Kaminskyy et al. The antifibrotic activity results revealed that compounds which significantly reduced the viability of fibroblasts did not possess antiproliferative or antineoplastic effects at a concentration range of 0.01-100 µM. Only compound (Z)-5-(4-chlorobenzylidene)-2-(4hydroxyphenylamino)thiazol-4(5H)-one (76), which possessed significant anticancer activity, displayed moderate antifibrotic action. However, xCelligence system testing of compounds confirmed that compounds (74), (75), (77) and (78) demonstrated most potent antifibrotic activity similar to standard drug pirfenidone and did not scavenge superoxide radicals [125]. 31
O
O O N
H3C N
H3 C S
N
O
N H
NH
S
N N
S F
O
N
F
(74)
H N S
(75)
F
O
CH2 O N
O
N S
N
N O
S
S HO
NH
S S
Cl
NH
N
(76)
O (77)
Cl N H
(78)
Figure 21: Thiazole derivatives as antifibrotic agents (74-78). 2.2.2
NF-ҡB inhibitors NF-kB and AP-1 are important transcription factors and promising targets for the development of anti-cancer therapeutics associated to variety of genes namely IL-6, IL-8, MMP-9, COX-2, and MCP-1. Similarly, the translation initiation factors, eIF-4E, eIF-4F, and eIF-4G, as well as mTOR have been shown to play a significant role in tumour progression. The thiazole compounds have been found as inhibitors of NF-ҡB that may be useful in treating cancer. 2-Thiazol-5-yl-3H-quinazolin-4-one derivatives were scrutinized by Giri et al. in order to explore their potential as inhibitors of NF-ҡB, AP-1 mediated transcription and eIF-4E mediated translational activation which play a pivotal role in initiation and progression of cancer. Some of the test compounds produced a very good dose dependent inhibition of NFҡB and AP-1 mediated transcriptional activity. Compounds (79a), (79b) and (79e) strongly inhibited (>70%) TNFα induced NF-ҡB gene expression at the 3.3 µM concentration. Similarly compounds (79c) and (79d) were also found to have IC50 of 3.3 and 5.5 µM, respectively. Of these, only compound (79c) was found to be inhibiting cell growth at 3.3 µM by more than 20% against FaDu cell lines [126].
32
R2 N
N S
R1 NH
N O
Active compound 79c; R1; CH3, R2; CH3, R3; Cl Inhibitory Conc.; 3.3 µM
R3
Compd.
R1
79a; 79b; 79c; 79d; 79e;
4-ClC6H4 COOC2H5 CH3 C6H5 4-ClC6H4
R2
R3
C6H5 OCH3 CH3 Cl CH3 Cl CH3 Cl C6H5 Cl
(79)
Figure 22: Thiazole derivatives as NF-ҡB inhibitors (79). 2.2.3
PI3K/mTOR inhibitor Rapamycin is a clinically successful (mTOR) allosteric inhibitor, and its derivatives of rapamycin have been successfully developed for treatment of cancer. Recently, Xie et al. have produced rapamycin-benzothiazole hybrid derivatives for their anti-cancer activity against Caski, CNE-2, SGC-7901, PC-3, SK-NEP-1 and A-375 human cancer cell lines. Some of the tested derivatives were found as potent anticancer agents. Specifically compound (80) was most active displaying IC50 values of 8.3 (Caski) and 9.6 µM (SK-NEP-1), respectively. Moreover, it was found that compound (80) causes G1 phase arrest, induces apoptosis in the Caski cell line and significantly decreased the phosphorylation of S6 ribosomal protein. Compound (80) was able to inhibit the cancer cell growth by obstructing the mTOR pathway and might be suitable drug candidate to develop new mTOR inhibitor [127]. Ali et al. scrutinized in vitro anticancer activity of a novel series of imidazo[2,1-b]thiazoles bearing pyrazole derivatives against NCI-60 cell panel at a dose of 10 µM. The biological testing indicated that against the CNS SNB-75 and Renal UO-31 cancer cell lines, compounds (81-83) demonstrated most potent activity with a percentage cell growth of 59.16-110.76 %. These compounds (81), (82) and (83) also showed significant results for toxicities, druglikeness, and drug score profiles and have considerable correlations with rapamycin (mTOR inhibitor). In silico studies, revealed that compounds (81-83) could be considered as promising leads for further robust scientific exploration and development of more potent anticancer agents in future [128]. Xie et al. investigated 1-alkyl-3-(6-(2-methoxy-3-sulfonylaminopyridin-5-yl)benzo[d]thiazol2-yl)urea derivatives for their inhibitory activity against PI3Ks and mTORC1 as well as antiproliferative activities against HCT116, MCF-7, U87 MG and A549 cell lines. Compound (84) with a methoxy group at the 2nd-position of pyridine ring exhibited most potent 33
antiproliferative activity against all the cell lines (IC50; 0.30-0.45 µM). Further, cell based activity results revealed that compound (84) exhibited significant activities against PI3K and mTORC1. The inhibitory activities against PI3Kα, PI3Kβ and PI3Kγ were higher than the standard drug BEZ235. The results also strongly recommended that 1-alkyl-3-(2,3disubstituted pyridin-5-ylbenzo[d]thiazol-2-yl)urea can be used as PI3K and mTOR dual inhibitors [129]. Li et al. developed nineteen derivatives of 2-methoxy-3-phenylsulfonylaminobenzamide and 2-aminobenzothiazole fragments and reported their anticancer activity against HCT-116, A549, MCF-7 and U-87 MG cell lines. These compounds were also evaluated as PI3K/ AKT/mTOR inhibitors. Interestingly, compound (85) exhibited most potent anticancer activity with IC50; 0.50-4.75 µM against all the cell lines used when compared with the standard drug BEZ235. Western blot assay revealed that compound (85) significantly block the PI3K/AKT/mTOR pathway and decreases the tumour growth [130]. Hayakawa et al. aimed to synthesized imidazo[1,2-a]pyridine derivatives as potent PI3 kinase p110α inhibitors. Seqential optimization of compound 3-{1-[(4-fluorophenyl)sulfonyl]-1Hpyrazol-3-yl}-2-methylimidazo[1,2-a]pyridine afforded thiazole derivative (86) which exhibited antiproliferative activity (IC50; 0.21 µM) against A375 cells, suggesting that PI3K p110α is a potential target in cancer treatment (exhibiting 60-fold selectivity for p110α). In HeLa cells, furthermore, compound (86) suppressed tumour growth by 37% in HeLa xenograft mice when dosed intra-peritoneally at 25 mg/kg once daily for 2 weeks with no significant toxicity [131]. 4’, 5-Bisthiazole variant of an (S)-proline-amide aminothiazole-urea drivatives as selective phosphatidylinositol-3 kinase alpha inhibitors (PI3K inhibitors) were identified by Fairhurst et al. Among the screened derivatives, derivatives (87) and (88) were capable of inhibiting signaling through the PI3K pathway for greater than 8 hours demonstrated most potent and selective PI3Kα inhibitor within an IC50 values range of 0.009-0.29 µM. Thus, (S)-prolineamide aminothiazole-urea generated tricyclic series hold the significance to be used as selective PI3Kα inhibitor [132].
34
S H
Cl S N
OCH3
N
NC
CH3 H N S
(82)
CH3 F O S HN O O
O
N
N N CH 3
N
O
O
N
N
S
H3C
N
S
O O
CH3
N N
N
(81)
N
(80)
N
O
O
O N H3C
N
O
H3C
F
(83)
(84) S
H3C O
Cl
N H3C S
N N
N
O S
CH3
O
O
S
H3C
N H
S
N N
S
HN N
O
CF3 CH3 CH3
N
N
(86)
H2N
N S
HN
O NO2
(85)
NH
NH
CH3 O
H2N
N
BEZ235
N
O
HN N
O
N
CH3 H3C CH3
O (87)
H2N
(88)
Figure 23: Thiazole derivatives as PI3K/mTOR inhibitor (80-88). 2.2.4
Apoptotic/angiogenesis agents Dysregulation of the programmed cell death process (apoptosis) is a hallmark of many types of malignancies. Apoptosis comprises of intrinsic or extrinsic pathways in which caspase-3 plays a central role in both types of apoptotic pathways. Keeping this in mind a novel compound 2-chloro-N-(2-(2-(5-methylpyridin-2-ylamino)-2-oxoethylthio)-benzo[d]thiazol-6yl) acetamide (89) (YLT322) was synthesized by Xuejiao et al. as potent anti-tumour agent via inducing apoptosis both in vitro and in vivo against human cancer cells. After compound YLT322 (89) treatment, it was observed that apoptosis was associated with activation of caspases-3 and -9, but not caspase-8 due to concomitant increase in their cleavage, indicative of enzyme activation. Addition of the irreversible inhibitors, Z-VAD-FMK (caspase inhibitors) and Ac- LETD-FMK(caspase-9 inhibitors) significantly decreased the percentage of apoptotic cells after treatment with compound YLT322 (89), suggesting that cell apoptosis induced by YLT322 (89) may be dependent on caspase activation. Moreover, YLT322 (89) suppressed the growth of established tumours in xenograft models in mice without obvious side effects [133]. 35
Choi et al. examined a novel compound N-(5-(2-bromobenzyl) thiazole-2-yl) benzofuran-2carboxamide (90) for its cytotoxicity and anticancer effect on cell growth, apoptosis, and angiogenesis against human HCC cells (HEPG2, Hep3B, and Huh-7 cells). HCC cells were exposed to four concentrations from 0.1 to 20 µM of (90) for 48 h whereas sorafenib, a commercial drug was used as standard. These results showed that compound (90) not only inhibited cell growth and angiogenesis, but also induced apoptosis of human HCC cells in a dose-dependent manner [134]. In search of potential chemotherapeutics for cancer treatment Tantaka et al. herein reported a new series of novel 2-aryl-amino-4-(3′-indolyl)thiazoles. In vitro cytotoxicity study was done against a panel of human cancer cell lines namely lung (A549), cervix (HeLa), liver (HEPG2) and breast (MCF-7 and MDA-MB-231) at micromolar IC50 range. Out of the test compounds, compound (91) was acknowledged as the most potent cytotoxic agent against MCF-7 breast cancer cells with an IC50 value of 1.86 µM and low toxicity on normal human cells as compared to doxorubicin. Flow cytometry mechanism showed that (91) induced ROSmediated (Reactive Oxygen Species) apoptosis in MCF-7 cells through the mitochondrial apoptosis pathway [135]. The anticancer activity of new series of spirooxindole-pyrrolothiazole-containing compounds were studied by Lotfy et al. All the newly synthesized compounds were scrutinized for their in vitro activity against breast cancer cell line MCF-7 and K562-leukemia. Compound (92) was found to be the most potent against MCF-7 breast cancer cells and K562-leukemia, with IC50 values of 15.32 ± 0.02 and 14.74 ± 0.7 µM, respectively as compared to 5-FU. Annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) (AV/PI) dual staining assay revealed that compound (92) increased the apoptosis percentage two fold at concentration of 10 µM [136]. Kumar et al. developed a multicomponent synthesis of molecular hybrid of pyrazole and thiazole in order to find out their in vitro apoptosis inducer activity on granulosa cells of ovarian antral follicles of goat (Capra hircus). Among the test compounds, only compound (93) exhibited maximum DNA damage or potency to induce apoptosis with percentage of apoptosis 25.61 ± 2.95 in comparison with control (5.14 ± 0.44). Hence, it can be concluded that substituted phenyl ring attached to the thiazole and pyrazole scaffolds contributed as apoptosis inducer activity in terms of electronic and steric parameters [137].
36
The pro-apoptotic and anti-angiogenic effect of newly synthesized thiazole, pyridine, pyrazole, thiazolopyridine and pyrazolopyridine progesterone derivatives was studied by Yahya et al. These compounds were evaluated for their cytotoxic effect against human breast cancer cells (MCF-7) using tamoxifen as standard drug. Among the synthesized thiazolecontaining compounds, derivatives (94a) and (94b) showed anticancer activity (IC50; 5.28 & 5.87 µM) against MCF-7 cancer cell line as compared to tamoxifen (IC50; 3.53 µM). From SAR viewpoint, introduction of a methyl group to the steroid moiety in compound (94a) contributed more potent compound than a phenyl group in compound (94b). It has been found that these compounds displayed significant pro-apoptotic effect through the down regulation of BCl-2, survivin, and CCND1 genes [138]. A series of pyridinyl-thiazolyl carboxamide derivatives was identified by Zhou et al. in order to examined angiogenesis in human umbilical vein endothelial cells (HUVECs) by in vitro method. The biological data revealed that compound (95) found to inhibit angiogenesis by suppressing key angiogenesis signaling pathways, such as ERK, JNK and FAK-Src etc. In addition, compound (95) also showed excellent effect on a breast tumour growth model with the dosage of 30 mg/kg [139].
37
S O
S
H3C
S
NH
O
O
(89) YLT322
(90)
S
HO N N
HN S
H
N
N H
H
(91)
H3C O
Br
N HN
O
N
N
Cl
H N
Br
O (92)
N
H N
Cl
N S
N N
Br
Compd.
R
94a; 94b;
-C6H5 -CH3
(93)
H3C
S
N N
H H O
H
(94)
N N O CH3
N H
N
CH3 HN S
H3C N
O (95)
Figure 24: Thiazole derivatives as apoptotic/angiogenesis agents (89-95). 2.2.5
RSK2 inhibitors RSK2 has been identified as a potential oncology drug development target based on its role in MAP kinase signalling and more recently on its importance for the RAS-ERK pathway as it effects tumour cell invasion. In this context, Andreani et al. carried out synthesis of a new series of imidazo[2,1-b]thiazole guanylhydrazones and screened them as RSK2 inhibitors and tumour growth inhibitors. Analogues with F substitution (96a) and with Br substitution (96b) depicted most potent tumour cell growth inhibitors with mean pGI50 6.25, 6.51 respectively either due to transport across cell membranes or might be critical nature of RSK2. Further to study the effect of RSK2 kinase on tumour cell growth, a cell-based assay was performed on 38
human breast cancer line MCF-7 and normal human breast line, MCF-10A. Of these, compounds (96a) and (96b) have the lowest IC50 selectively against MCF-7, MCF-10A and the biomarker GSK3 evidenced that compounds significantly affected the RSK2 target in cells [140]. NH2 HN N N
R S
NH
NO2 N
Compd.
R
96a; 96b;
F Br
(96)
Figure 25: Thiazole derivatives as RSK2 inhibitors (96). 2.2.6
DNA intercalating agents DNA-intercalating ligands as anti-cancer drugs have developed greatly since the clinical success of doxorubicin (adriamycin) and daunorubicin, and dactinomycin. Despite a great deal of 'rational design' of synthetic DNA-intercalators has been achieved by researchers, only few compounds have proved clinically successful. The design and synthesis of new drugs is focused on intercalators which have two intercalating groups linked via a variety of ligands, and synergistic drugs, which combine the anticancer properties of intercalation [141]. The heterocycles such as thiazole-containing compounds fused with some other heterocycles have possessed DNA intercalating properties which is summarized as below. In vitro antiproliferative activity of a novel series of arylidene-hydrazinyl-thiazole-containing compounds was depicted by Grozav et al. against MDA-MB231 and HeLa cancer cell lines using MTT assay. Generally, the viability of cancer cell lines decreased as the concentration increased. Among the test compounds, 2-(2-benzyliden-hydrazinyl)-4-methylthiazole derivative (97a) was highly potent against both the cell lines MDA-MB-231 (IC50; 3.92 µg/ml) and HeLa (IC50: 11.4 µg/ml) than the standard chemotherapeutic cisplatin (IC50; 17.28, 26.12 µg/ml) and oxaliplatin (IC50; 14.09, 23.17 µg/ml), respectively. Further, DNA Intercalation study was conducted on compounds (97a-97d) through the gel electrophoresis experiment which indicated that antiproliferative activity of these derivatives against MDAMB231 and HeLa cancer cell lines is independent of DNA intercalation [142]. 9-Anilinothiazolo[5,4-b]quinoline derivatives for their in vitro cytotoxic activity and DNAintercalation studies were evaluated by Reyes-Rangel et al. The cytotoxic activity was 39
performed against one cervical cancer line (HeLa), two colorectal cancer cell lines (SW-480 and SW-620) and one leukaemic cell line (K-562). Generally leukaemic cell line (K-562) and cervical cancer line (HeLa) were more susceptible towards the test compounds within a IC50 values range of 5.69-85.8 µM. Among the test compounds, compound (98) exhibited maximum activity against K-562, while against HeLa compound (99) was most effective with IC50 values of 4.5 and 12.06 µM, respectively. By studying the substitution pattern, it was observed that substitution with methylthio group improves the intercalation of the derivatives into the DNA, but did not render the cytotoxic activity of the compound [143]. Two mononuclear copper (II) terpyridine complexes namely, [Cu(Btptpy)(ClO4)](ClO4) 100a, and [Cu(Bttpy)(ClO4)](ClO4) 100b, Btptpy (L1) = 4’-(Benzothiophene)-2,2’:6’,2”terpyridine, Bttpy (L2) = 4’-(Benzylthiazolyl)-2,2’:6’,2”-terpyridine) were developed by Manikandamathavan et al. in order to find out their antiproliferative activity against HEPG2 and triple negative CAL-51 cell line. The IC50 value of the two complexes have been found to be 0.28 ± 0.01 µM (100a) and 0.29 ± 0.01 µM (100b) in the case of CAL-51 cell line in comparision to cisplatin (8.22 µM). In addition, complexes (100a) and (100b) showed more cytotoxic effect with IC50; 0.31±0.03 µM (100a) and 0.27±0.01 µM (100b) on HEPG2 than the cisplatin (24.29 µM). DNA interaction studies showed that both the complexes bind DNA via intercalation [144]. Ar HC N
Compd.
R1 N N H
S
Active compound 97a; Ar; Phenyl; R1; CH3, R2; H IC50; 3.92 µg/ml
R2
(97)
N
S
R2
CH3 C6H5 CH3 C6H5
H H H H
X
S N
S
NH
N
N
N Cl (98)
R1
NH
N
N
C6H5 4-OCH3C6H4 4-OHC6H4 4-OHC6H4
97a; 97b; 97c; 97d;
N
Cl
Ar
(99)
Cu (ClO4) (100)
N Compd.
X
100a; 100b;
H N
Figure 26: Thiazole derivatives as DNA intercalating agents (97-100). 2.3
Miscellaneous anticancer activity of thiazole-containing compounds 40
Besides different modes/site of action, a number of thiazole-containing compounds have been screened for their antiproliferative/cytotoxic activity against numerous cancer cell lines such as breast cancer (MCF-7), lung cancer (HeLa), cervix cancer (KB/HELA), ovarian carcinoma (SK-OV-3), brain cancer (SF-268), nonsmall-cell lung cancer (NCl-H460), adenocarcinoma colon cancer (RKOP-27), Neuroblastoma (SKNMC), Human hepatocarcinoma (Hep-G2), human colon carcinoma (HT-29), breast carcinoma (BT-20) and leukaemia (CCRF-CEM) cells, etc. A series of steroidal derivatives possessing a D-ring substituted benzamidothiazole were synthesized by Fan et al. in order to find out their anticancer activity against PC-3 (human prostate cancer cell line) and SKOV-3 (ovarian cancer cells). All the screened derivatives demonstrated mild to moderate antiproliferative activity. Among the tested derivatives, (101) showed the maximum activity with 59% inhibition at concentration of 50 µM against d SKOV-3 cells in comparison to reference compound etoposide (VP-16) [145]. Kavitha et al. scrutinized 2-(4-(2-oxo-2H-chromen-3-yl)thiazol-2-yl)-3-arylacrylonitriles for their in vitro anti-hepatoma activity against HepG2 cell lines. Most of the compounds exhibited good to excellent cytotoxicity in HepG2 cells. Compounds (102a) and (102b) were found to possess excellent inhibition having IC50 values of 2.33 ± 0.004 and 2.89 ± 0.004 µM, respectively. Further, docking with B-Cell Lymphoma-2 (BCL-2) domain revealed that compound (102a) have shown one hydrogen bond interaction with BCL-2 domain with highest docking score of 57.22 k.cal/mol and bond length of 1.325 Å [146]. Mohammadi-Farani et al. introduced a series of N-phenyl-2-p-tolylthiazole-4-carboxamide derivatives and assessed their in vitro anticancer activity against human cancer cell lines such as Neuroblastoma (SKNMC), Human hepatocarcinoma (Hep-G2) and Breast cancer (MCF-7 cell) using doxorubicin as standard. All the test compounds were unable to yield anticancer activity against MCF-7 cell line. Only compounds (103a) bearing para nitro (IC50; 10.8 ± 0.08 µM) and (103b) bearing meta chlorine (IC50; 11.6 ± 0.12 µM) pharmacophoric features showed maximum cytotoxic effects towards SKNMC and Hep-G2 cell lines respectively [147]. Zablotskaya et al. have introduced a new series of N-[1,3-(benzo)thiazol-2-yl]-ω-[3,4dihydroisoquinolin-2(1H)-yl] alkanamide derivatives and evaluated them against monolayer tumour cell lines: human fibrosarcoma (HT-1080), mouse hepatoma (MG-22A), and normal mouse fibroblasts (NIH 3T3). From the SAR viewpoint, compound (104) was most effective 41
against hepatoma MG-22A with LC50 4 µg/ml (NO-induction ability and non-toxic at LD50 517 mg/kg) and moderately active against fibrosarcoma HT-1080. Whereas, halogen substituted compound was most active against human fibrosarcoma (HT-1080) (NOinduction ability and non-toxic at LD50; 1879 mg/kg). Substitution in compound (105c) with bulky groups, such as p-CH3O-C6H4 at C4 position of thiazolyl ring possessed positive effect on antitumour activity (LC50; 28 µg/ml) [148]. A microwave assisted synthesis of a novel series of sulfones of a 5-nitrothiazoles and their in vitro antiproliferative activity against two different cancer cell lines, CHO and HEPG2, was performed by Cohen et al. All the test compounds exhibited substantial inhibition against HEPG2 cells (7.7 µM ≤ HEPG2 CC50; ≤ 25.6 µM) as compared to standard drug doxorubicin (HEPG2 CC50 = 0.2 µM). Compounds (106a-106e) (dichlorinated) possessed high cytotoxicity against both the cell lines at (1.0 µM ≤ CC50 ≤ 2.5 µM) than dihydrogenated derivatives when compared with doxorubicin. Biological screening data clearly indicated that the methyl group next to sulfonyl attributied antiproliferative activity in this series against human liver tumour cells [149]. Antitumour activity of
two novel series of nortopsentin analogues of thiazolyl-bis-
pyrrolo[2,3-b]pyridines and indolyl-thiazolyl-pyrrolo[2,3-c]pyridines against the NCI-60 cell line panel was performed by Carbone et al. Primarily all the compounds were evaluated against approximately 60 human tumour cell lines derived from 9 human cancer cell types at a single dose 10-5 M. Further compounds (107) and (108) were selected and screened at five concentrations 10-4 M-10-8 M. Biological data showed that compounds (107) and (108) exhibited antitumour activity with GI50 values ranging from (0.81–27.7 and 0.93–4.70 µM respectively). Generally, indolyl-thiazolyl-pyrrolo[2,3-c]pyridine derivative (108) was more potent than thiazolyl-bis-pyrrolo[2,3-b]pyridines derivative (107). The cell cycle alteration mechanism suggested that (107) caused a dose-dependent and (108) induced a dosedependent accumulation of cells in G2/M phase [150]. A novel series of 2-phenyl-4-trifluoromethyl thiazole-5-carboxamide derivatives for their anticancer activity against A-549, Bel7402, and HCT-8 cell lines were executed by Cai et al. All the synthesized derivatives exerted moderate inhibition at 5 µg/ml when compared with standard drug 5-fluorouracil. Out of the test compounds, compound 4-chloro-2methylphenylamido substituted thiazole (109) bearing 2-chlorophenyl group on heterocyclic
42
moiety, showed highest activity (48%) against A-549 as compared to standard drug (57%) [151]. Various N-benzyl substituted (((2-morpholinoethoxy)phenyl)thiazol-4-yl)acetamide clubbed thiazole-containing compounds were synthesized by Fallah-Tafti et al. and subjected for Src kinase inhibitory activities and for anticancer activities against human colon carcinoma (HT29), breast carcinoma (BT-20) and leukaemia (CCRF-CEM) cells. Biological findings revealed that compound (110a) with GI50 values of 1.34 µM and 2.30 µM against NIH3T3/cSrc527F and SYF/c-Src527F cells, compound (110b) in the inhibition of cell proliferation of BT-20 and CCRF cells at concentration of 50 µM were found to be the most potent compounds. From SAR viewpoint, the presence of a substituent at position 4 of benzyl ring such as 4-F, 3,4-dicl2, or 4-CH3 were essential for strong anticancer activity [152]. Taher et al. have introduced some novel heterodiazole annulated imidazo[2,1-b]1,3,4oxa/thiadiazolone, 1,3,4-oxa or thiadiazole[3,2-a]pyrimidine diamine and 1,3,4-oxa or thiadiazole-3- piperidino-1-propamide derivatives. In vitro antitumour activity was carried out against a panel of 60 cell lines at concentration ranges of 0.01 to 100 µM. Out of test compounds,
compound
2-phenyl-7,7a-dihydro-imidazo[2,1-b][1,3,4]thiadiazol-5(6H)-one
(111) showed broad-spectrum antitumour activity having effectiveness toward numerous cell lines and was most active compound of this series with GI50, TGI, and LC50 values of 6.0, 17.4, and 55.1 µM, respectively, when compared with standard drug 5-flurouracil [153]. A series of cantharidin analogues with a structure of aminothiazole and anhydride were evaluated by Yeh et al. for their anticancer and cytotoxic effects on human hepatocellular carcinoma cell (HCC) lines HEPG2, Sk-Hep1 and then compared with primary cultured rat hepatocytes. All the screened derivatives exhibited no cytotoxicity against primary cultured rat hepatocytes as compared to their parent compounds. Of these, anhydride derivative promoted apoptosis in HEPG2 (IC50; 62 µM) and SK-Hep1 (IC50; 151 µM) cell lines. However thiazole derivative (112) was able to promote apoptosis in HEPG2 (IC50; 92 µM)
43
O HN O
N
Active compound 102a; R; -OCH3 IC50; 2.33 µM
N
N
F
S
S Compnd. 102a; 102b;
(101)
R
O
Compd.
N
NH
N(CH2)nCONH
Compd. 105a; 105b; 105c; 105d; 105e; 105f;
N
N (105)
R
(104) Cl Cl S N O R
O
S
CH3
Compd.
(106)
R p-NO2 m-Cl
R
n
S
S
O2 N
103a; 103b;
CH3
(103)
N(CH2)CONH
(102)
S
R
Active compound 103a; R; p-NO2 IC50; 10.8 µM
O
O
R
4-OCH3 3,4-diOCH3
R
106a; 106b; 106c; 106d; 106e;
Active compound 105c; R; p-CH3O-C6H4 LC50; 28 µg/ml
1 1 1 1 . HCl 2 2
Br
C6H5 p-CH3-C6H4 p-Cl-C6H4 p-Br-C6H4 p-F-C6H4
Active compound 106b; R; p-CH3-C6H4 CC50; 1.0 µM
H CH3 p-CH3OC6H4 p-CH3OC6H4 H p-CH3OC6H4
S N
N N
N
HN
Br
CH3 (107)
N S Cl N
F N
HN
F
NH
(108)
F NH
S Cl
O O
O
O
N N
Cl
S
(109)
N N H
S
N
(111)
O N
N O
S (110)
H N O
(112) R
Compd.
R
110a; 110b;
H F
Figure 27: Thiazole derivatives as cytotoxic agents (101-112). cell lines. Both the compounds anhydride and (112) were found to have similar anticancer effect. The SAR study concluded that removal of the bridging ether oxygen on the ring 44
decreased the hepatocyte cytotoxicity and the anhydride modified structure promoted apoptosis in human hepatocellular carcinoma cells [154]. A series of new imidazo[2,1-b]thiazole-containing compounds were scrutinized by Gursoy et al. in order to explore their potential for cytotoxic activity. For all the synthesized compounds preliminary anticancer assay was performed, subsequently compounds which passed the criteria for activity were further evaluated against the full panel of 60 human tumour cell lines at a minimum of five concentrations (10-fold dilutions). Amongest them, compound (113a) revealed noticeable effects on a prostate cancer cell line (PC-3, log10 GI50 value < 8.00). Structure analysis showed that 4-hydroxy substitution on phenyl group of compound (113a) contribute most active compound in series. However, movement of hydroxyl group from 4th position to 2nd position on phenyl ring leads to (113b) which demonstrate anticancer activity against most of the cell lines [155]. Prasanna et al. have designed and synthesized a series of 2-arylcarboxamide substituted (S)6-amino-4,5,6,7-tetrahydrobenzo[d]thiazole-containing compounds and screened for their anti-leukaemic activity against human leukemia cells, K562 and CEM at 10, 50 and 100 µM. Among the test compounds, compound (114) having a tert-butyl substitution at para position showed excellent inhibition against K562 and CEM cells with IC50 values of 4.52 µM. Further compound (114) was assessed for cytotoxic activity against 293T cells (human embryonic kidney epithelial cells). From the observation of their structures and SAR, it was concluded that compounds with ortho substitution or no substitution or substitution with bulky groups exhibited poor inhibition of anti-leukaemic cells, while compounds with substitution at meta and para positions showed reasonable inhibition of anti-leukaemic cells [156]. Synthesis of a novel thiazolone-based compounds containing 5-aryl-3-phenyl-4,5-dihydro1H-pyrazol-1-yl moiety as potential anticancer agents was done by Havrylyuk et al. Most of the synthesized compounds showed promising anticancer activity on leukemia, melanoma, lung, colon, CNS, ovarian, renal, prostate and breast cancer cell lines evaluated at single concentration of 10-5 M. Out of the test compounds, pyrazoline substituted derivative (115) containing di-methoxy along with hydroxyl groups on phenyl ring demonstrated highest activity on non-small cell lung cancer cell line HOP-62 and colon cancer cell lines HT 29 (having highest selectivity) with log GI50 - 6.37, and - 6.37, respectively. SAR study
45
concluded that substitution on 5th position of thiazolone ring and p-OH on benzylidene part improves the potency of the compounds [157]. Antitumour activity of various N-bis(trifluoromethyl)alkyl-N’-thiazolyl and -benzothiazolyl urea derivatives were depicted by Luzina et al. against several human cancer cell lines. Analogue (116) against UO-31 (renal cancer, log GI50 -5.66), and SR (leukemia, log GI50 5.44) of human cancer cells exhibited potent cytotoxic activity as compared to standard drug 5-fluorouracil, nonfluorinated urea and non-urea bis-trifluoromethylated benzothiazole [158]. Al-Omary et al. introduced a novel series of thiazolo[2,3-b]quinazoline, and pyrido[4,3d]thiazolo[3,2-a]pyrimidine and evaluated for their in vitro antitumour activity at 60 cell lines panel assay and compared with 5-FU standard drug. Biological findings indicated that compounds (117-119) revealed notable broad-spectrum antitumour activity. Out of them, compounds (117) and (118) were nine fold more active as compared to 5-FU (GI50, TGI, and LC50 values = 2.5, >100, >100 µM and 2.4, 9.1, 36.2 µM, respectively. On the other hand, compounds (119a) and (119b) were seven fold more active as compared to 5-FU (GI50, TGI, and LC50 values = 2.9, 12.4, 46.6 µM and 3.0, 16.3, 54.0 µM, respectively. From SAR viewpoint, the synthesized 6,7,8,9-tetrahydro-5H-pyrido[4,3-d]thiazolo[3,2-a]pyrimidine derivatives (117-119) were observed as more potent antitumour agents in comparision to their 6,7,8,9-tetrahydro-5H-thiazolo[2,3-b]quinazolines (117) counterparts [159]. Chen et al. have developed a new and efficient method for the synthesis of N-(2-chloro-6methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl)]-2-methyl-4-pyrimidinyl]-amino)]1,3-thiazole-5-carboxamide (120) popularly known as anticancer drug dasatanib. The reaction described a chemoselective α- bromination of β-ethoxyacrylamide followed by a one-pot treatment with thiourea to give 2-aminothiazole-5-carboxylamide in excellent yield. With this new method, they were able to avoid the generation and handling of the moisture sensitive organometallic intermediates and protection/deprotection steps [160]. Screening of several novel 5-arylidene-4-thioxo-thiazolidine-2-one derivatives for their antimicrobial activity and antiproliferative activities against two human carcinoma cell lines (NCI-H292 and HEp-2) was done by Gouveia et al. Generally, compounds (121), (122) were observed to be more sensitive to NCIH292 cell lines than the HEp-2 cell lines. However, these compounds demonstrated lower cytotoxicity as compared to vincristine standard drug (IC50; 0.04, 0.003 µg/ml for NCI-H292 and HEp-2, respectively). From the biological data 46
the antiproliferative activity was only observed at 45.03% (122g) for NCI-H292 cell lines and at 30.10% (122c) for HEp-2 cell lines. Furthermore, none of the compounds was able to produce 50% inhibition of cell proliferation at the highest dose (10 µg/ml) [161].
CH3 H3C CH3
R CH2CONHN=CH
H2N
N
N
Br N
Compd.
S
113a; 113b;
(113)
N H
O
(114)
4-OH 2-OH F
O
HO
OH
S
F CH3 O HN F HN
F F
CH3
O
N N N
S
R
F
S N
CH3
O
(116)
(115)
S N
S
N
N
OCH3
N
H3CO
OCH3
H3CO
OCH3
N H3C
OCH3 (117)
(118)
H3CO
R
S
S N
O N
H3CO
OCH3
H3CO H3C
(119)
Cl
CH3
N HO
N
R
119a; 119b;
H CH3
S
N H (121)
OCH3
N
N
Compd.
N
O
HN
N N H
Active compound 122g; R; 2-Cl Inhibitory Conc.; 10 µg/ml
S
Dasatanib (120)
OH C 3
HN S
S
(122)
R
Compd.
R
122a; 122b; 122c; 122d; 122e; 122f; 122g; 122h; 122i; 122j;
2-F 3-F 4-F 2-Br 3-Br 4-Br 2-Cl 3-Cl 4-Cl 2,4-Cl2
Figure 28: Thiazole derivatives as cytotoxic agents (113-122).
Various pyridazino-, pyrimido-, quinazolo-, oxirano- and thiazolo-steroidal derivatives were produced by Elmegeed et al. and screened for their potential chemotherapeutic anti-breast 47
cancer agents against human breast cancer cells (MCF-7). All the test compounds exhibited potent broad spectrum cytotoxic activity as compared to standard drug doxorubicin (Dox) (IC50; 4.5 µM) after 48 h incubation. Compound (123) displayed most potent inhibitory effect on MCF-7 growth with IC50; 2.5 µM than doxorubicin (IC50; 4.5 µM). Remarkably, compounds (123-124) showed significant depletion with various intensities in gene expression of breast cancer related genes (VEGF, CYP19 and hAP-2γ). From SAR viewpoint, the attachment of heterocyclic moiety such as thiazole to steroidal moiety leads to potent cytotoxic activity in compound (123) followed by the copper complexes compound (124) and pyrimidinyl androstane derivatives [162]. Several
novel
5-(2-Aminothiazol-4-yl)-4-phenyl-4H-1,2,4-triazole-3-thiol
containing
derivatives were synthesized and were screened for their anticancer activity by Hassan et al. Four human tumour cell lines namely: hepatocellular carcinoma HEPG2, caucasian breast adenocarcinoma MCF-7, colon carcinoma HCT-116, and lung carcinoma A549 were used to ascertain the potency of test compounds, while doxorubicin was used as standard drug. Compounds (125) and (126) were equipotent to doxorubicin with LC50 values of 17.4-25.0 µM against the four tumour cell lines. Compound (126) have emerged as most potent compound by exhibiting LC50 values of 23.5 and 17.4 µM against colon carcinoma HCT-116 and caucasian breast adenocarcinoma MCF-7 cell lines, respectively. It was concluded that substituent at the 2-amino group of the thiazole nucleus or at the 4-phenyl ring attached to the 1,2,4-triazole function have great influence on antitumour activity [163]. Hassan et al. introduced a novel series of 2-acetamido- or 2-propanamido-4-(4-substituted phenyl)-1,3-thiazole-containing compounds and tested for their in vitro antitumour activity at a single dose of 10 µM. Most of the test compounds showed significant antitumour activity at given dose than the standard antitumour drug 5-FU. Compounds (127a) and (127b) bearing the chloro group were the most potent anticancer agents which was about nine and seven fold potent with MG-MID GI50, TGI, and LC50 values of 2.8, 11.4, 44.7; and 3.3, 13.1, 46.8, respectively, as compared to standard drug. From the above findings, it was concluded that the three carbon chain connecting the thiazole nucleus to the secondary amines had significant influence on antitumour activity [164]. Several 2-substituted benzimidazoles consisting 2-[(4-oxothiazolidin-2-ylidene) methyl and (4-amino-2-thioxothiazol-5-yl) benzimidazoles; 2-[(4-fluorobenzylidene and cycloalkylidene) cyanomethyl] benzimidazoles; 2-[(4- or 5-oxothiazolidin-2-ylidene, 4-substituted thiazolyl-248
ylidene and [1,3]thiazin-2-ylidene) cyanomethyl] benzimidazoles were synthesized and screened for in vitro anticancer activity by Refaat et al. The anticancer activity was performed against human hepatocellular carcinoma cell line (HEPG2), human breast adenocarcinoma cell line (MCF-7) and colon carcinoma cell line (HCT-116) while doxorubicin was used as standard antitumour drug (10 µg/ml). Among the thiazolecontaining compounds, 2-thiazolylbenzimidazole derivative (128) and oxothiazolidin-2ylidenecyanomethyl benzimidazole (129) were the most potent compounds possessing broad spectrum of activity against all three cell lines with IC50 values of 0.55, 3.51, 4.23; 0.93, 2.83, 3.72 and IC90 values of 7.53, 14.06, 14.02; 7.89, 12.63, 12.02, respectively. In conclusion, all the test compounds were found to possess potential antitumour activities against all the tested tumour cell lines [165]. Fluorinated 2-(4-aminophenyl)benzothiazole analogues as a potential in vitro cytotoxic agents against various cell lines were introduced by Hutchinson et al. Generally these compounds showed better cytotoxic activity in the range of micromolar concentration as (GI50 < 1 µM). Biological evaluation revealed that compound (130) bearing 5-F substitution was potently in vitro cytotoxic (GI50 < 0.01 µM) against NCI cell panel (NCI-H266, NCIH460, HCC-2998, IGROV1, OVCAR-4, OVCAR-5, TH-10, MCF-7, T47-D). Interestingly, compound was metabolically stable and form no exportable metabolites in the presence of these cells, approving that oxidative metabolism of 2 in the 6-position completely blocked by 5-fluorination [166]. A new series of arylidene-hydrazinyl-thiazole-containing compounds was developed by Grozav et al. and were assayed for their in vitro antiproliferative activity against two human carcinoma MDA-MB231 and HeLa cell lines using MTT assay. According to IC50 data five thiazole-containing compounds have shown significant inhibition as compared to the standard drugs platinum drugs, cisplatin and oxaliplatin. Compound 2-(2-benzyliden-hydrazinyl)-4methylthiazole (131) against MDA-MB-231 (IC50; 3.92 µg/ml) and HeLa (IC50; 11.4 µg/ml), compound (132) with an IC50 value of 11.1 µg/ml against HeLa cell lines were emerged as potential leads and hence could be investigated for further scientific exploration for the treatment of cancer [167]. Some pyrazole-based 1,3-thiazole and 1,3,4-thiadiazole derivatives were synthesized and assayed for their in vitro anticancer activity by Dawood et al. These compounds were screened against human hepatocelluar carcinoma (HEPG2), human breast cancer (MCF-7) 49
and human lung cancer (A549) and compared with doxorubicin (0.877, 1.172, 0.41 µM respectively) standard drug. Among all the test compounds, the starting precursor i.e. compound (133) (8.348 10.08 7.743 µM) and 1,3,4-thiadiazole (134) (8.107 10.03 8.68 µM) of series were almost equipotent, exerting the pronounced anticancer activity. SAR studies have concluded that isosteric replacement between the compounds of the series control the anticancer activity [168]. In search of novel anticancer agents twenty one new benzothiazole bearing 2-thioxo-4thiazolidinone derivatives were synthesized by Mosula et al. and screened in vitro for anticancer activity at 60 human tumour cell lines. Newly synthesized compounds showed antitumour activity on renal cancer, non-small cell lung cancer, ovarian cancer cell lines. Out of the tested, compound 2-{2-[3-(benzothiazol-2-ylamino)-4-oxo-2-thioxo-thiazolidin-5ylidenemethyl]-4-chlorophenoxy}-N-(4-methoxyphenyl)-acetamide (135) was found to be most active with average logGI50 and logTGI values -5.38 and -4.45 respectively. Compound (135) was selected as matrix for further drug design of 4-thiazolidones as possible anticancer agents [169]. Desai et al. screened some thiazole clubbed 1,3,4-oxadiazole derivatives for their in vitro antimicrobial and cytotoxic activities. The antimicrobial activity results revealed that compounds (136a), (136b) (antibacterials) and (136c) (antifungal) were emerged as most potent lead compounds in the series displaying MIC 12.5-250 µg/ml. Further, in vitro cytotoxicity of compounds (136) were performed against human cervical cancer cell line (HeLa) by the MTT colorimetric assay. It was observed that none of the test compounds exhibited any significant cytotoxic effect on HeLa cells, which suggested that these compounds have a great potential for their in vivo use as antimicrobial agents [170]. Twelve novel 17-(2’-oxazolyl)-and 17-(2’-thiazolyl)-androstene derivatives were synthesized by Zhua et al. and assessed as inhibitors of 17 α-hydroxylase-C17,20-lyase (P45017α). Generally, the potent inhibitors of P45017α could be used in effective treatment of prostate cancer. The results showed that the compounds containing 17-(2’-oxazolyl) (56.0% inhibition) and 17-(2’-thiazolyl) (23.7%) demonstrated inhibition against P45017α, although they were less potent than ketoconazole. Compound 17-(5’-methyl-2’-thiazolyl) (137, 72.1%) had similar activity to ketoconazole and was as much as potent to 17-(5’-isoxazolyl)-pregna4,16-diene-3,20-dione (L-39) inhibitor among this series [171].
50
Mohareb et al. carried out synthesis of some naturally occurring pregnenolone containing thiophene, thiazole, thieno[2,3-b]pyridine derivatives. All the newly synthesized heterocyclic steroids were studied for their cytotoxicity against three human tumour cell lines namely breast adenocarcinoma (MCF-7), non-small cell lung cancer (NCI-H460) and CNS cancer (SF-268). Some of the test compounds showed much higher inhibitory effects than the standard drug doxorubicin (GI50 0.04 ± 0.008, 0.09 ± 0.008, 0.09 ± 0.007 µM). Among the test compounds, thiazole-containing compounds (138a), (138b) showed the highest inhibitory effect against MCF-7 (GI50; 0.6 ± 0.4, 0.2 ± 0.2 µM), NCI-H460 (GI50 0.2 ± 0.08, 0.6 ± 0.02 µM), SF-268 (GI50; 0.8 ± 0.4, 0.4 ± 0.08 µM), respectively. However cytotoxicity of the thieno[2,3-b]pyridinyl androstene derivatives was found much higher in the series [172]. In continuation to the search of novel anticancer agents Mohareb et al. synthesized some pyrazole, pyridine, thiazole and thiophene derivatives of pregnenolone. In vitro cytotoxic activity was executed against breast adenocarcinoma (MCF-7), non-small cell lung cancer (NCI-H460) and CNS cancer (SF-268). By comparing the cytotoxicity of the thiazolecontaining compounds (139a-139c), it was found that the 5-hydroxythiazole derivative (139c) has greater cytotoxicity against non-small cell lung cancer (NCI-H460, GI50; 0.01 ± 0.003 µM) and breast adenocarcinoma (MCF-7, GI50; 0.02 ± 0.001 µM) than the 5phenylthiazole derivative (139a) and the 5-methylthiazole derivative (139b), which was much higher than the standard drug doxorubicin (NCI-H460, GI50; 0.09 ± 0.008; MCF-7, GI50; 0.04 ± 0.008) [173].
51
CN
NO3
H3C
N S
HN
H
NO3 N
CN
(123)
(125) S
H
S
(124)
H
NH
HS Compd. 127a; 127b;
S Cl
R Cl CH3
N
(126)
NH2
H N
N
(127)
S
S
(128) S
N H3C
N
NH
S
N
N
N
OCH3
N N H
(131) (132)
NO2
CH3 N
H2N
NH2 S
S O
N
(130)
H3C
O
S N H
O
(129)
F
OH
N
N Cl
NH O
N
N
H N
N
N
O
Cl
O
O
H AcO
N
N
CH3
S
H
H
HS
CH3
N
N
N
H
AcO
S
NH2 Cu NH2
H
O
N S
(133)
O
H3C
N
N
N N
N S
N N
S
O
CH3
O
N
O
H3C
CH3
CH3
(134)
O S
N H O
S S
Cl
N N H (135)
O
H N
S N
R
O N
S N N H3C
Compd. 136a; CH3 136b; 136c; O
H N
R F OCH3 NO2
(136)
Figure 29: Thiazole derivatives as cytotoxic agents (123-136). Using key intermediates 1-(5 amino-3-hydroxy-1H-pyrazol-1-yl)-2-chloroethanone and 3-(5amino-3-hydroxy-1H-pyrazol-1-yl)-3-oxopropanenitrile some thiophene, pyran, thiazole and fused heterocyclic derivatives were synthesized by Mohareb et al. The in vitro antitumour activity was assessed against breast adenocarcinoma (MCF-7), non-small cell lung cancer (NCI-H460) and CNS cancer (SF-268) while doxorubicin was used as standard drug. Among the newly synthesized pyrazole-thiazole-containing compounds 2-(4-(5-amino-3-hydroxy52
1H-pyrazol-1-yl)-3-phenylthiazol-2(3H)-ylidene)-malononitrile (140a) and 2-(4-(5-amino-3hydroxy-1H-pyrazol-1-yl)-3-phenylthiazol-2(3H)-ylidene)-pentan-2,4-dione (140b) exhibited most potent inhibitory effects with GI50 0.01-0.03 µM [174]. In an another investigation Mohareb et al. utilized hydrazide-hydrazone for the synthesis of coumarin, pyridine, thiazole and thiophene derivatives and performed their antitumour activity against breast adenocarcinoma (MCF-7), non-small cell lung cancer (NCI-H460) and CNS cancer (SF-268).
Biological findings revealed that the thiazole derivative (141)
possessed moderate antitumour activity as compared to the standard drug doxorubicin (MCF7, GI50; 42.8 ± 8.2 nM; NCI-H460, GI50; 94.0 ± 8.7 nM, and SF-280, GI50; 94.0 ± 7.0 nM) [175]. A series of some novel 2-(benzo[d]thiazol-2-yl)-8-substituted-2H-pyrazolo[4,3-c]quinolin3(5H)-ones was synthesized by Reis et al. and screened for their in vitro antiproliferative activities against four human cancer cell lines: (MDA-MB-435) breast, (HL-60) leukemia, (HCT-8) colon and (SF-295) central nervous system. Biological findings revealed that compounds (142a) and (142b) displayed excellent cytotoxicity against three cell lines with IC50 values lower than 5 µg/ml. While, none of the compound exhibited haemolysis in mouse erythrocytes up to 250 µg/ml. Thus, it can be concluded that the most active compound (142b) against breast cancer (MDA-MB-435) can be used as a promising lead molecule for anticancer drug design [176]. Chaniyara et al. identified a new series of 2,3-bis(hydroxymethyl)benzo[d]pyrrolo[2,1b]thiazoles and their bis(alkylcarbamate) derivatives and assessed for their in vitro antiproliferative activity against human leukaemia and various solid tumour cell growth. Among the newly synthesized derivatives, compounds (143-145) displayed potent therapeutic efficacy against MX-1 in xenograft model, which was used for further evaluation of anticancer activity. Compounds (143-145) were shown to have most significant cytotoxicity with IC50 values of 0.07, 0.05 and 0.08 µM, respectively, against CCRF-CEM cell growth. The compounds showed complete tumour remission at a dose of submaximal tolerated dose of 20 mg/kg, and were selected as a lead compound for studying its anticancer activity [177]. A novel one-pot procedure for the synthesis of 2-(N-pyrrolidinyl)-4-amino-5-(3’,4’,5’trimethoxybenzoyl)thiazole have been developed by Romagnoli et al. The compounds were studied for their antiproliferative effects against murine leukaemia (L1210) and mammary carcinoma (FM3A) lines and the human T-leukaemia lines Molt/4 and CEM and the human 53
cervix carcinoma HeLa line. Only compound (146) exhibited submicromolar antiproliferative activity (GI50 0.18-0.37 µM) against all tested lines, whereas other derivatives generally had little activity (GI50 >10 µM) than the reference compound CA-4 (GI50 0.002-0.042 µM) [178]. Some novel benzoxazole derivatives were synthesized and assessed for their in vitro anticancer, anti-HIV-1 and antimicrobial activities by Rida et al. Antitumour activity was carried out against 60 human cell lines derived from nine clinically isolated cancer types (Leukaemia, non-small cell lung, colon, CNS, melanoma, ovarian, renal, prostate and breast cancer) at different concentrations. Comparing the antitumour activity of benzoxazole bearing thiazole-containing compounds (147a) and (147b), demonstrated potent activity against maximum tumour cell lines (GI50; TGI; and LC50; values < 100 µM & having selectivity ratio of 0.22-1.16). Specifically compound (147c) was most effective against CNS (GI50 values 21.5 and 12.9 µM), leukemia K-562 (GI50, 0.47 µM) and melanoma UACC-62 (GI50 0.45 µM) cancer cell lines. While, compound (147a) exhibited most potent antitumour activity against prostate cell line (GI50, 17.9 µM) [179]. Synthesis of some novel 1,3,4-oxadiazole derivatives containing different pharmacophores/ heterocyclic rings for antitumour and cytotoxic activities was executed by Bondock et al. The newly developed compounds were screened against four cancer cell lines (namely HEPG2, WI-38, VERO, MCF-7) and some of them exerted promising in vitro antitumour activity. The resultant data suggested that incorporation of a thiazole ring in compound (148) to 1,3,4oxadiazole skeleton displayed improved antitumour activities than the pyrazole and thiophene ring systems. Compound (148) demonstrated most potent activity against lung fibroblasts (WI 38; GI50 17.3 µg/ml), hepatocellular carcinoma (HEPG2; GI50 12.4 µg/ml), kidney carcinoma (VERO, GI50; 15.8 µg/ml) and moderate activity against breast cancer (MCF-7; GI50; 26-50 µg/ml). Besides, compound (148) exhibited high protection against DNA damage induced by the bleomycineiron complex, thus diminishing chromogen formation between the damaged DNA and TBA [180].
54
R
CH3
N S
CH3
Compd.
R
138a; 138b;
Cl Br
N N N
CH3
S
HO
(138)
OH
(137)
R1 HO
Compd.
R
139a; 139b; 139c;
O
Ph CH3 OH
HN N
N N
N
R2
S
CN
NH2
(140)
S CH3
Active compound 139c; R; OH GI50; 0.01µ µM
N
Ph
R
Compd.
R1
140a; 140b;
CN CN
R2 COCH3 COCH3
(139)
HO
N
NH
O
O
Compd. S
N H
S
N
N
R
142a; 142b;
CH3
S
N
H2N
N
N
CH3 Br
(142) Cl
(141) F HO O
H3C CH3
H3C
H3C O
N N
N S
H3C HO
OH
N O
N CH3
O
N
O OH CH3
(143)
OH O
N S
H3CO
N
O
CH3
O H3C H2N
N (146)
CH3
(145)
OH CH3
F Active compound 147c; R; 4-ClC6H4 GI50; 0.45 µΜ
H2N N
N
OH CH3
CHO S
S O
N
(144) H3CO
O
N
N O
OH
N
HO HO
CH3
O N (147)
N S
R S
Compd.
R
147a; 147b; 147c;
(CH2)3CH3 CH2C6H5 4-ClC6H4
Figure 30: Thiazole derivatives as cytotoxic agents (137-147).
55
The
anticancer
activity
of
novel
2-[(2-oxo-2H-[1,2,4]triazino[2,3-c]quinazolin-6-
yl)thio]acetamides with thiazole and thiadiazole fragments were inspected by Kovalenko et al. The cytotoxic activity evaluation was done by means of bioluminescent test of the luminescent bacteria Photobacterium leiognathi at the concentration gradient of 0.025-0.25 mg/ml. Preliminary in vitro anticancer assay was performed against a panel of 60 cancer cell lines derived from nine different cancer types: leukemia, melanoma, lung, colon, CNS, ovarian, renal, prostate, and breast cancers at a fixed concentration of 10 µM. Among the test compounds, compound (149) possessed potent anticancer activity against the cell lines of colon cancer (GI50 0.45-0.69 µM), melanoma (GI50 0.48-13.50 µM) and ovarian cancer (GI50 0.25–5.01 µM) with most favourable selective index 3.16 against ovarian cells [181]. Some indeno[1,2-c]- pyrazol(in)es substituted with sulfonamide, sulfonylurea(-thiourea) and some derived thiazole ring systems were synthesized by Rostom et al. The newly synthesized compounds were assayed for their in vitro antitumour activities against 60 cell lines of nine tumour subpanels, including leukaemia, non-small cell lung, colon, CNS, melanoma, ovarian, renal, prostate and breast cancer cell lines. Among the thiazole-containing compounds (150) and (151) showed potential broad spectrum antitumour activity and low selectivity index against almost all the tested subpanel tumour cell lines (GI50 < 100 µM). However, 4-(3-(4chlorophenyl)-4H-indeno[1,2-c]pyrazol-2-yl)-benzenesulfonamide having no thiazole moiety in its structure; proved to be the most effective analog with the utmost cytostatic and cytotoxic potentials (TGI and LC50 (MG-MID) concentrations of 33.1 and 66.1 µM, respectively). Generally, the oxidized pyrazoles exhibited superior antitumour activity than their parent pyrazoline analogs [182]. Laczkowski et al. developed some thiazole-based nitrogen mustard and screened them as anticancer agents against human cancer cells lines (MV4-11, A549, MCF-7 and HCT116) and normal mouse fibroblast (BALB/3T3). Among the derivatives, 152a, 152b, 152c, 152d and 152e were found to exhibit high activity against human leukaemia MV4-11 cells, with IC50 values of 2.17-4.26 µg/ml. While, compounds (152c) and (152e) showed strong activity against MCF-7 and HCT-116 with IC50 values of 3.02-4.13 µg/ml. Compound (152c) was 5-8 times lower toxic against normal mouse fibroblast BALB/3T3 cells than against cancer cell lines. The molecular modelling studies revealed that possibility of human topoisomerases inhibition might be the mechanisms which attributed the anticancer activity of these derivatives [183].
56
As a part of ongoing studies in developing new anticancer agents, a series of bifunctional ethyl 2-amino-4-methylthiazol-5-carboxylate derivatives were synthesized by Rostom et al. and evaluated for their preliminary in vitro antimicrobial and anticancer activities. Out of the test compounds, nine were evaluated for their in vitro anticancer activity against NCI 60 cell panel including leukemia, non-small cell lung, colon, CNS, melanoma, ovarian, renal, prostate and breast cancer cell lines at fixed dose of 10 µM. The results revealed that, compound (153) proved to possess a broad spectrum of anticancer activity against 29 of the tested 60 subpanel tumour cell lines, particularly effective against the non-small cell lung cancer (Hop-92), ovarian cancer (IGROV1) and melanoma (SK-MEL-2) cell lines (GI% 64.2, 72.9 and 77.6, respectively). From SAR viewpoint, it was found that derivatization of the 2-amino group, rather than the conversion of the ester function into carboxamido and acid hydrazide moieties imparts superior cell growth inhibitory activity [184]. Kok et al. introduced novel cantharimide analogues bearing 2-aminobenzothiazole in order to find out their cytotoxicity on SK-Hep-1 hepatoma cells. Compound (154a) (CAN036) showed a comparable MTS50 activity (50% of MTS reduction ability, 3-6 µg/ml) as that of cantharidin (MTS50 = 6.25-12.5 µg/ml) and cisplatinum (MTS50 = 6.25–12.5 µg/ml) on SKHep-1 hepatocellular carcinoma cell line. While compound (154b) bearing methyl group demonstrated a weaker activity against cancer cell line (MTS50 = 12.5-25 µg/ml). SAR studies demonstrated that the introduction of electron withdrawing group of 2aminobenzothiazole at 6-position attributed to enhanced cytotoxicity to cancer cells whereas reducing the non-malignant cell toxicity [185]. Thiazol-5-carboxamide derivatives were scrutinized by Cai et al. in order to explore their potential as anticancer agents against A-549, Bel7402, and HCT-8 cell lines. Out of test compounds, 4-chloro-2-methylphenyl amido substituted thiazole containing the 2chlorophenyl group on 2nd position (155) of the heterocyclic ring displayed highest activity (48% inhibition) against A-549 as compared to standard drug 5-fluorouracil (57% inhibition) at a concentration of 5 µg/ml. The title compounds exhibited no inhibition or low inhibitory effect against Bel7402 and HCT-8. Only compound (156) (40% inhibition) displayed moderate inhibitory activity against HCT-8 [186]. Liu et al. presented a novel modified chiral 2-(ethylthio)-thiazolone derivatives and evaluated for their in vitro anticancer activities against five different cancer cell lines using the MTT assay. Most of the synthesized derivatives have shown potential anticancer activities against 57
EJ, PC-3, HepG-2 and Jurkat cancer cell lines with an IC50 range of 20-30 µM. Out of these test compounds, compounds (157a) and (157b) having one ortho-halogen substituted on phenyl group showed noteworthy inhibitory effects on the Jurkat with IC50 values of 17 and 19 µM, while a weaker inhibitory activity (IC50; 38 µM, 41 µM) on the breast cancer cell MDA-MB-231 was reported [187]. A small library of enantioselective largazole analogs was developed by Zeng et al. in order to assess their antiproliferative activity against HCT-116, A549, HEK293 and HLF cancer cell lines at a concentration of 10 µM. Generally, no activity was found with cis geometry of the alkene against either human tumour cell lines or normal cell lines. Compounds (158a) and (158b) were equipotent to largazole against normal cell lines, while in compound (158c) the replacement of Val 1 with tyrosine produced much improved selectivity for cancer cell lines (HCT-116: GI50 0.39 µM; A549: GI50 1.46 µM) over the normal cell lines (HEK293: GI50 > 100 µM; HLF: GI50 >100 µM). The resultant data suggested that the tyrosine residue of compound (158c) could be responsible for the selectivity towards cancer cells over normal cells [188]. Shi et al. screened twenty novel benzothiazol-2-thiol derivatives for their in vitro anticancer activity against a panel of different types of human cancer cell lines. Among the screened derivatives, pyridinyl-2-amine linked benzothiazol-2-thiols exhibited potent and broadspectrum inhibitory activities. Compound (159a) exerted highly potent anticancer activity on SKRB-3 (IC50;1.2 nM), SW620 (IC50; 4.3 nM), A549 (IC50; 44 nM) and HEPG2 (IC50; 48 nM) about 10-1000 times potent than the standard. Further, compound (159a) induced apoptosis in HEPG2 cancer cells. However, against A431 (IC50; 20 nM) compound (159b) exhibited the most potent antitumour activities from the series [189]. Mabkhot et al. developed biologically important thieno[2,3-b]thiophene derivatives and evaluated for their in vitro β-glucuronidase and α-glucosidase inhibitory activities, DPPH radical scavenging activity, cytotoxicity and anticancer activity. Comparing the anticancer activity of thiazole-containing compounds, compound (160) exhibited moderate anticancer activity with (IC50; 24.213 ± 0.29 µM) against PC-3 cell lines as compared to standard drug doxorubicin (IC50; 0.912 ± 0.12 µM). All the other screened compounds were observed to be non-cytotoxic and showed >30% inhibition of PC-3 cancer cell lines [190].
58
O
NC S
H3C
O
N N
N
CH3
N
N N
N H
O
N N
N S
S
N O
(148)
N
N S O2
HN
(149)
O
S
(150) Cl
N N
N
N S O2
HN Active compound 152c & 152e; IC50; 3.02-4.13 µg/ml
S Cl Cl
(151)
HN S
N Compd.
R1
N O S N O H
N NH (152)
Compd.
N S (154)
R O
NH
OCH3 CH3
S S
N
F3C
N
CH3
(157)
Compd.
R
157a; 157b;
Cl Br
(155)
O
S
R
O
N
N
Cl
H N
S
CH3
(156)
Cl
O
HN Ts
Cl
S NH H N
Cl
N
S
Cl
4-F 4-CN 4-CF3 4-OCH3 2,3,4,5,6-F5
R
154a; 154b;
R
O
O CH3
(153) CH3
O CH3 N
F3C
R1
152a; 152b; 152c; 152d; 152e;
CH3
O
O O
N
O
Cl
S
O
NH (159)
Compd. 158a; 158b; 158c; H3C
O
R CH(CH3)2 C6H5 4-OH-C6H4
R O
O S
S NH O
N O
N
S
Compd.
R
159a; 159b;
Br Cl
N H
(158)
Figure 31: Thiazole derivatives as cytotoxic agents (148-159). New rhodacyanine analogues containing the pyridinium, isoquinolinium and quinolinium ring system were developed by Li et al. and assessed for antitumour activity against human lung cancer cell line (H460). Nearly every tested compound exhibited superior antitumour activity with IC50 values ranging from 0.006-9.2 µmol/l as compared to the lead compound 59
MKT-077. Among the test compounds, the most promising compound (161) (IC50; 0.006 µmol/l) was found to be 216.7 times more active than MKT-077 (IC50; 1.3 µmol/l). SAR study concluded that change in the heteroaromatic ring linked to the rhodanine ring via N–N covalent bond enhanced the antitumour activity following the order: quinolinium > isoquinolinium > pyridinium. While, replacing the substituent methyl to cyclopropyl groups on the rhodanine ring, and hydrogen to chloride groups on 6th position of benzothiazole ring have little or no influence on antitumour activity [191]. Luo et al. presented a novel series of thiazolylbenzimidazole derivatives and scrutinized for their antitumour activity against SMMC-7721 and A549 cell lines. Generally, all the known derivatives demonstrated excellent antitumour activity. One compound, (162) containing a flexible and basic alkyl chain showed significant in vitro anticancer activity against both SMMC-7721 cell (IC50; 1.14 µM) and A549 cell (IC50; 2.43 µM) comparable to taxol (IC50; 1.42, 0.63 µM). Data suggested that thiazolylbenzimidazole compounds with no quinone moiety could also serve as potent antitumour agents [192]. Hybrids of macrosphelides and epothilones with a thiazole side chain were designed and assessed for antitumour and apoptosis-inducing activities by Matsuya et al. Some of these hybrid analogues having thiazole substituent were found to exhibit prominent apoptosisinducing activity against human lymphoma cells than parent natural macrosphelides. Among the thiazole containing compounds, compound (163) demonstrated most potent early apoptosis and negligible secondary necrosis at 1 µM concentration. Rest of all the screened derivatives were moderate to poor in apoptosis-inducing activity [193]. Kanda et al. contributed novel C-8 ester derivatives of leinamycin which exhibited significant antitumour activity against the several experimental models. It was found that number of ethylene glycol ether units (n) were essential for both in vitro & in vivo antiproliferative activity against HeLa S3 cells & sarcoma 180, respectively. Specifically, compound (164) showed significant antitumour activity against Lu-65 (T/C 0.20), against sarcoma 180 (T/C 0.30) [194]. Chakrabarty et al. have introduced regioselective synthesis of novel 2-alkylamino- and 2alkylthiothiazolo[5,4-e]- and -[4,5-g]indazoles and evaluated for their anticancer activity against A549 cell line. Biological study revealed that compound (165) exhibited most potent
60
activity (GI50 72.1 µmol, 78.8 µmol) at a concentration of 25 & 100 µmol, respectively against human lung carcinoma A549 cell line [195]. Cardoso et al. described new phthalimide derivatives endowed with dual immunomodulatory activity and antiproliferative activity. Antiproliferative activity was carried out against human cancer cell lines SF-295, HCT-8, MDA/MB-435 and LYMP at concentration of 50 µg/mL and lymphocytes at 5 µg/ml. Biological results have shown that compounds (166a) and (166b) were potent immunosuppressive agents with cell proliferation inhibition rates ranging from (IC50; 7.5, 5.3 µg/ml for SF-295) and (IC50; 5.8 and 5.2 µg/ml for HCT-8), respectively as compared to positive control doxorubicin. On the other hand, compounds (166a) and (166b) displayed IC50; 9.4 and 7.7 µg/ml, respectively, against human lymphocytes [196]. Soares et al. screened a new chiral 6-hydroxymethyl 1H, 3H-pyrrolo[1,2-c]thiazoles for their in vitro anticancer potential against colorectal adenocarcinoma, melanoma and breast adenocarcinoma cells. Among the test compounds, compound (167) possessed IC50; 62.9 µM, 15.4, 2.4 µM against A375 melanoma cells, WiDR colorectal adenocarcinoma cells and MCF-7 breast cancer cells, respectively. Similar results were obtained for 6-hydroxymethyl(R)-pyrrolo[1,2-c]thiazole benzylcarbamate (168) with IC50; 2.2 µM against MCF-7 breast cancer cell lines and IC50; 8.7 µM against colorectal adenocarcinoma cell lines. Thus, selectivity for breast cancer cell lines was observed for both pyrrolo[1,2-c]thiazole-containing compounds (167) and (168) [197]. Carbone et al. introduced nortopsentin analogues of thiazolyl-bis-pyrrolo[2,3-b]pyridines and Indolyl-thiazolyl-pyrrolo[2,3-c]pyridines and demonstrated their in vitro antiproliferative activity against the NCI full panel of human cancer cell lines and STO and MesoII cells, derived from human diffuse malignant peritoneal mesothelioma (DMPM). Among all the test compounds, compounds (169) and (170) exhibited antiproliferative activity against most of the human cell lines at GI50 values from micromolar to submicromolar (GI50 0.81-27.7 and 0.93-4.70 µM, respectively). Analogues (169) and (170) exhibited potent activity against human HTC-116 colorectal carcinoma cells and HCT-116 cells (GI50 2.91 and 2.35 µM,), (GI50 33.55 ± 2.31 µM and 13.15 ± 0.95 µM), respectively. Taking in account the GI50 values measured by NCI, the cytotoxic effects of the nortopsentin analogues appeared timedependent [198]. In an another study, Parrino et al. also identified a new series of nortopsentin analogues of 3[4-(1H-Indol-3-yl)-1,3-thiazol-2-yl]-1H-pyrrolo[2,3-b]pyridines and checked their in vitro 61
anticancer activity against various cell lines namely K-562, SR,NCI-H522, NCI/ADRRES,MDA-MB-435. The basic structure of nortopsentin contains the imidazole ring which was replaced by thiazole and indole moieties. Out of the tested analogues, analogues (171a171b) showed potent antiproliferative activity and high selectivity against 60 human tumour cell lines of NCI panel with micromolar to nanomolar GI50 13.0-0.03 and 14.2-0.04 µM, respectively. Both the compounds exhibited a concentration-dependent accumulation of cells in the sub G0/G1 phase while confined viable cells in G2/M phase [199]. Anticancer activity of a series of 2,4-disubstituted-1,3-thiazoles linked with pyrazoline scaffolds was done by Sadashiva et al. Anticancer activity was carried out against A549 and MCF-7 human cancer cell lines. Generally, the compounds bearing chloro atom at the para position of phenyl ring A such as (172-174) exhibited superior anticancer activity with IC50 values of 7.5, 5.0 and 5.0 µM respectively as compared to the standard drug cisplatin (IC50; 10.0 µM). Further, compounds were also evaluated for their in vitro antimicrobial activity and some of them possessed good activity against the strains used [200]. In a study, Mirza et al. have scrutinized several novel substituted aryl-thiazole (SAT) derivatives for their cytotoxicity against four cancer cell lines namely MCF-7 (ER +ve breast), MDA-MB-231 (ER –ve breast), HCT-116 (colorectal) and HeLa (cervical). Among them, compounds (175a-175b) demonstrated improved toxicity to the four cell lines with IC50 values 5.37 ± 0.56 to 46.72 ± 1.80 µM as compared to the standard drug doxorubicin (IC50; 1.56 ± 0.05 µM). The results revealed that substituted aryl thiazoles (175a) and (175b) might be a suitable lead compounds for further investigation in cancer treatment [201].
62
H3C
CH3
H2N
N
NH2
N
S
S
N+ IN
CH3 N S
S
S
S
H3C
N
N H
S
N
H3C
N
N
CH3
O
(160)
O
N
(162)
(161) O S
O
O
H3C
O N
-
O
O
O
H3C
CH3
S
S
O S+
(165)
N
O
OH
O H3C
H N
N
NH
S
O
N H
N
NH
(163)
N
N
O
O O
H3C O
O
CH3
HO
(164)
CH3
S O
Cl
Compd. 166a; 166b;
(166)
S
Cl OCH3
H N
H N
(167)
Br N
O
Br
N
S
O
Cl
S NH
N
(170)
CH3 N
N
N
N
H N HO
N
R
(169)
H N
S
S
O N H
N
N N
(168) H3C Compd.
R
171a; 171b;
CH3 H
Cl
N N N
N R
(172)
R1
Cl
S (171)
H N
S N
Cl
O N H
O
N N
O 2N
O
(173)
HN N
N N
S O Cl
N
HN NH
N (174)
O
R2
Compd.
R1
R2
175a; 175b;
2-NH2 4-Cl
4Cl 4-Br
S (175)
Figure 32: Thiazole derivatives as cytotoxic agents (160-175). Popsavin et al. reported new tiazofurin analogues bearing 2,3-anhydro functionality in the furanose ring and evaluated for their in vitro antitumour activity against various cell lines viz. 63
K562, HL-60, Jurkat, Raji, HT-29, MCF-7 and MRC-5. Remarkably, all three analogues (176-178) exhibit sub-micromolar cytotoxicity against K562 malignant cells, (IC50; 0.09 to 0.49 µM). Compound (176) and µ-homo-C-nucleoside (177) showed most potent cytotoxic activity against Raji cells, being almost 30-fold and 230-fold, respectively with respect to the reference compound tiazofurin. Compound α-homo-C-nucleoside (178) was most powerful antitumour agent against K562 cell line (33-fold) while inactive against Raji cells than tiazofurin (IC50; 16.02 µM). Interestingly, all these compounds were completely inactive against the normal MRC-5 cells [202]. Abdelgawad et al. executed synthesis and in vitro antiproliferative activity screening of certain novel thiazolidinone derivatives substituted with benzothiazole or benzoxazole. Newly synthesized compounds were scrutinized against human breast MCF-7 and liver HEPG2 cancer cell lines using doxorubicin (GI50 29.66 nM and 1.036nM) as a reference. pMethoxy- 5-benzylidine-4-thiazolidinone derivatives of benzoxazole (179a) (IC50; 0.027 nM) and benzothiazole (179b) (IC50; 0.026 nM) exhibited most potent antitumour activity against liver HEPG2 cancer cell line, respectively. On the other hand, compound (179c) against breast MCF-7 cancer cell line (IC50; 19 nM), while compound (179d) exhibited a broad spectrum antitumour activity against MCF-7 and HEPG2 cell lines with IC50; 36, 48 nM, respectively [203]. Some novel 1,3-thiazole-containing compounds containing hydrazide-hydrazone and carboxamide moiety were synthesized by He et al. Anticancer activity of synthesized compounds was carried out against MCF-7, HEPG2, BGC-823, Hela, and A549 cell lines using 5-Fu as standard drug. Some compounds exhibited superior activity, specifically, compounds (180a) and (180b) exhibit best cytotoxic activity with IC50 values of 2.21 µg/ml and 1.11 µg/ml against MCF-7, and HEPG2 cell lines, respectively. In addition, the flow cytometry analysis of compounds (180a, 180b) showed induced apoptosis in HEPG2 cells by S cell-cycle arrest [204]. Gomha et al. described a novel series of 3-[1-(4-substituted-5-(aryldiazenyl)thiazol-2yl)hydrazono)ethyl]-2H-chromen-2-ones for their in vitro cytotoxic activity against HaCaT cells (human keratinocytes). Among all the compounds, compound (181) possessed significant cytotoxic activity. MTT assay results of healthy cells HaCat cells incubated with 50 µL 0.5 mol compared to control compound (181) showed better time-dependent
64
cytotoxicity. However, the used concentration of (181) did not produce noteworthy cytotoxic effect on the healthy HaCaT cells [205]. In an another study, Gomha et al. examined some thiazoles, thiadiazoles, and pyrido[2,3][1,2,4]triazolo[4,3-a]pyrimidin- 5(1H)-ones incorporating triazole moiety for in vitro antitumour activity against MCF-7 and HEPG2 cell lines. The biological findings revealed that thiazole derivative (182) possessed potent antitumour activity against the human hepatocellular carcinoma cell line HEPG2 and the breast carcinoma cell line (MCF-7; IC50; 3.41 and 1.12 µM, respectively) while rest of the test compounds have shown moderate anticancer activities [206]. In continuation to the search of novel molecules to act as potential anticancer agents Gomha et al. reported coumarin derivatives containing pyrazolo[1,5-a]pyrimidine, tetrazolo[1,5a]pyrimidine, imidazo[1,2-a]pyrimidine, pyrazolo[3,4-d]pyrimidine, 1,3,4-thiadiazoles and thiazoles. Antiproliferative activities of newly synthesized compounds were done against various cell lines such as HSC-39, Caco-2 and Hep-G2. Resultant data of screened thiazolecontaining compounds revealed that compound (183) (with a chlorine atom as electronwithdrawing group on the aryl moiety) exhibited promising antitumour activity against liver carcinoma (HEPG2-1) with IC50 value of 3.50 ± 0.23 µM while rest of compounds showed moderate activity [207]. In an another study Gomha et al. introduced aryl azothiazoles and 1,3-thiazolidin-4-one derivatives and scrutinized for their in vitro antitumour activity against hepatocellular carcinoma HEPG2 cell lines using WST-1 proliferation assay. Out of the test compounds, compounds (184a-184c) have potent anticancer efficiency for hepatocellular carcinoma with low (IC50; 0.84 ± 0.04, 0.52 ± 0.03 and 0.5 ± 0.02 µM, respectively when compared to doxorubicin with molecular binding affinities of –24.85, –24.23, and –24.10 kcal/mol. The dose response curves of compounds (184b) and (184c) indicated the IC50 (the concentration of test compounds required to kill 50% of cell population) were 0.54 µM and 0.50 µM, respectively. Molecular docking results have showed that the groups like N=N, C=N, NH2 and OCH3 groups were most important for formation of the hydrogen bonds and hence for the enhanced anticancer activity [208]. Ghorab et al. reported synthesis of novel thiazolo[4,5-d]pyrimidines, thioxopropanoic acid ethyl ester 7 and 4-oxothiazolidine benzene sulfonamides. All the newly synthesized compounds were executed for their in vitro anticancer activity against liver cancer cell line 65
(HEPG-2) in which hCAII is over expressed and exhibited promising activity as compared to doxorubicin. Among test compounds, compounds (185), (186), and (187) (IC50; 43, 43, 46 µM) exhibited most potent anticancer activity at 10, 25, 50, 100 µM than doxorubicin (IC50; 32 µM). This activity was remarkably increased upon further investigation in combination with radiation (IC 50; 30, 30, 32 µM) [209]. Ramla et al. reported synthesis of 2-(1-benzyl-2-methyl-1H-benzimidazol-5-ylimino)-3(substituted)-thiazolidin-4-one
and
3-(2-methyl-1H-benzimidazol-5-yl)-2-substituted-
thiazolidin-4-one derivatives in order to find out their inhibitory activity against EBV-EA induction. Results of antitumour activities indicated that compound (188) having the thiazolidinone ring linked to the 5th position of the benzimidazole through imino nitrogen was found to be most effective in the series. Compound (188) was found to be more active than the non-cyclized thiourea derivatives having a benzyl or p-methoxyphenyl as substituents. However the cyclized compounds having alkyl or phenyl groups as substituents to thiazolidinone derivatives (other than compound 188) were least active [210]. Gududuru et al. reported synthesis of 2-aryl-4-oxo-thiazolidin-3-yl-amides and evaluated for their in vitro antiproliferative activity against five human prostate cancer cell lines namely DU-145, PC-3, LNCaP, PPC-1, and TSU, and in RH7777 cells (negative controls). Among the test compounds, compound (189) was identified as most potent compound as compared to 5-FU against RH7777 (IC50; 11.5 µM), DU-145 (IC50; 11.2 µM), PC- 3 (IC50; 6.5 µM), LNCaP (IC50; 7.9 µM), PPC-1 (IC50; 5.4 µM) and TSU (IC50; 6.4 µM), respectively with 2–5 fold lower selectivity compared to RH7777 cell line [211]. Tzanova et al. introduced novel synthetic benzophenone analogues and evaluated for their in vitro antioxidant activity against cancerous MCF-7 and the non-cancerous hTERT-HME1 mammary cells, and the H9c2 cardiomyoblastic cell lines. Compound (190) (IC20; 93.5 ± 6.8, 149.9 ± 4.3 µM for MCF-7, hTERT-HME1, respectively) displayed the significant antioxidant activity and low cytotoxicity below 100 µM. Compound (190) was found to be 1.5 times more potent than the reference antioxidant (a water soluble derivative of vitamin E) trolox (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid) at 100 µM [212]. A molecular docking-based screening of novel 2-(4-phenylthiazol-2-yl) isoindoline-1,3-dione derivatives against prostate cancer cell lines (PC-3 & LNCaP) was demonstrated by Saravanan et al. The compound (191b) bearing flouro group exhibited potent activity on 66
LNCaP (IC50; 5.96 ± 1.6 µM), and moderate activity against PC-3 cell lines as compared to standard drug bicalutamide. While the compounds, (191a) & (191c) were moderately active against the LNCaP cell line. It is evident that the substitution at position R1 with the groups OCH3, CN and NO2 were influenced by the better activities compared to other groups. Thus, it can be concluded that 4-substituted phenyl-1,3-thiazole core showed the greater anticancer activities compared to aromatic substitution on 1,3-thiazole at 5th position [213]. Novel thiazoloquinazoline derivatives were developed by Ghorab et al. in order to screen its biological potential against cytoprotective enzyme NAD(P)H: Quinone oxidoreductase in Hepa1c1c7 murine hepatoma cells. The thiazoloquinazoline (192) exhibited remarkable activity with 1.34 fold NQO1 inducer activity. It was worth mentioning here that incorporation of thiazole moiety within a heterocyclic ring system (quinazoline) increases the NQO1inducer potency. Rest of the synthesized compounds revealed weak NQO1inducer activity [214]. In an another study, Rahman et al. have synthesized three thiazole substituted coumarin derivatives and described their in vitro cytotoxicity study against Human Periodontal Ligament Fibroblast (HPDLF) cells using MTT assay. The cytotoxicity study revealed that coumarin derivatives containing the hydrazinyl thiazolyl group (193) exhibited less toxicity with a concentration of 5.51 µM to the inhibition concentration at 50% cell death (IC50) comparable to parent compound [215].
67
HO
O
S
O
O
N
HO
NH2
O
S
O
N
O
O
OH NH2
S
N
NH2
O (176)
(177)
O H N
N
(178) O
R2
O S
X N
R Active compound 179b; R; OCH3, X; S IC50; 0.026nM
Compd.
X
R
179a; 179b; 179c; 179d;
O S O S
OCH3 OCH3 Cl NO2
N
H N
N N O
CH3
N NH
N
N N
S
H3C S H3C
(183) NH S
O
H N
HN H
(185)
N
N
NH2
S
S
N
CH3 N
N
R
184a; 184b; 184c;
R H Cl OCH3
O
CH3
N
O
CH3
Active compound 184c; R; OCH3 IC50; 0.50 µM
O S NH2 O
H N
O H2N S O
(186) O
O
N
(184)
O S O NH2
N
R2 CF3 2,6-Cl2
Compd.
S N
R1 CF3 CH3
N
N
N
S
N H
N
O
CH3 Cl
N
CF3
(182)
CH3 N
Br
N
O
(181) O
N HN
H3C
H3C
O
H N
S
Compd. 180a; 180b; H3C
N
N
R1
N
(180)
(179)
S
O
N H HN
O S
N
N
S
(187)
O N H
C18H37
O2N
N S
(188)
(189)
Figure 33: Thiazole derivatives as cytotoxic agents (176-189). Recently, sixteen novel derivatives of 1-[(1R)-1-(6-fluoro-1,3-benzothiazol-2-yl)ethyl]-3alkyl carbamate were designed by Pejchal et al. In addition to their acetylcholinesterase
68
(AChE) and butyrylcholinesterase (BChE) inhibitor activity, compounds were also screened for their cytotoxic activity against SK-BR-3 cell lines. Among the tested four compounds (194a-194d), only (194b) at concentrations of 100 µM and 250 µM and (194d) at concentration 250 µM significantly (p ≤ 0.01) decrease viability with moderate selectivity in cell lines used. However, all the test compounds were able to produce low toxicity at 1-250 µM concentration range [216]. Grozav et al. scrutinized sixteen hydrazinyl-thiazolo arene ruthenium complexes and tested in vitro for their antiproliferative activity on cell lines namely HeLa, A2780, A2780 cis R along with a noncancerous cell line (HFL-1). All the complexes exhibited significant antiproliferative activity against three cell lines when compared with cisplatin and oxaliplatin. The complexes (195a) and (195b) were found to possess a significant reduction of cytotoxicity on the normal fibroblasts cell line HFL-1, with (IC50; 181 µM) and (IC50; 36.6 µM), respectively. Moreover the cytotoxicity of these complexes on HeLa cells was found very low (>100 µM), which clearly indicated that hydrazinyl-thiazole compounds have beneficial effect of complexation with arene ruthenium units [217]. Laczkowski et al. introduced ten thiazole-based nitrogen mustards and screened them against human cancer cells lines (MV4-11, A549, MCF-7 and HCT116) and normal mouse fibroblast (BALB/3T3). Antiproliferative activity data revealed that compounds have varied degree of activity against the cancer cell lines. Compound (196a) has shown most potent activity against human leukemia MV4-11, MCF-7, HCT116 and BALB/3T3 cells with IC50 values of 2.17 µg/ml, 3.42 µg/ml, 3.02 µg/ml, 3.2 µg/ml, respectively than the standard drug cis-platin. However one compound (196b) was also found potent against MCF-7 cells with IC50 values of 3.02 µg/ml as compared to the cis-platin (IC50; 2.46 µg/ml). From the SAR viewpoint, substituents
(NHSO2CF3)
(196b)
and
(NHSO2C6F5)
(196a)
imparts
the
strong
antiproliferative activity in almost all tested cancer cell lines MV4- 11, A549, MCF-7 and HCT116 [218]. Wu et al. contributed a novel series of 5-(benzo[d][1,3]dioxol-5-ylmethyl)-4-(tert-butyl)-Narylthiazol-2-amines and tested for their antitumour activities against HeLa, A549 and MCF7 cell lines. Generally, the test compounds showed promising anticancer activity against all the cell lines below 5 µM. Compound (197a) exhibited potent activities against HeLa and A549 cell lines with IC50 values of 2.07 ± 0.88 µM and 3.52 ± 0.49 µM, respectively. Compound (197b) (IC50; 2.06 ± 0.09 µM) was the most active compound against A549 cell 69
line, while compound (197c) (IC50; 2.55 ± 0.34 µM) showed the best inhibitory activity against the MCF-7 cell line [219]. O
R1
H N
HO
O N
O S
OH
N
Active compound 191b; R1; CN, R2; F IC50; 5.96 µM
R2
S O
(190) (191)
Compd.
O
H3C
O
N S
O HN N
N
(192)
191a; 191b; 191c;
O
N
+ O Cl
R Compd.
HN O
194a; 194b; 194c; 194c;
S (194)
R
H
OCH3 OCH2CH3 OCH2CF2Cl OCH2CF2CHF2
R O S O HN
N
S N
N H (196)
196a; 196b;
R 2,3,4,5,6-F5 4-CF3
Ru N
S
N H
CH3
(195)
Compd. 195a; 195b;
Cl
Cl-
O
N
R
Cl
Compd.
OCH3 F CN F NO2 F
H3C
N
R2
O
S
(193)
F
R1
R 2,4-Cl2 2-Cl
N H3C Compd. 197a; 197b; 197c;
H3C
R 3,5-(CF3)2 3-Cl 4-NO2
CH3 O
N R
S O
NH (197)
Figure 34: Thiazole derivatives as cytotoxic agents (190-197). Balanean et al. have introduced novel N’-2-(2-methylamino)thiazol-4-yl)acetohydrazidehydrazone derivatives and performed their antiproliferative activity against the cell lines namely Hs578T, HeLa and HEPG2. Among the test compounds, compound (198) having substitution of 3-formylchromone in C-6 position was proved to be most potent with IC50 values of 0.823 µM, 5.077 µM, 4.950 µM corresponding to HeLa, HEPG2 and Hs578T cells, respectively [220]. A new series of series of N-{(1-(4-(4-bromophenyl)thiazol-2-yl)-3-substituted-phenyl-1Hpyrazol-4-yl)methylene}-1H-1, 2, 4-triazol-3-amines were synthesized and screened for their 70
antiinfective and cytotoxic activities by Bansal et al. Out of the test compounds, compound (199) bearing a p-NO2-phenyl have been emerged as most potent by exhibiting cytotoxic activity GI50 value of 1.2 µg/ml against HeLa cell lines as compared to adriamycin (GI50, <10 µg/ml). On the other hand, GI50 value were observed >80 µg/ml against the human breast cancer cell lines (MCF-7) [221]. Anticancer activity of benzimidazole-thiazolidinedione derivatives against human cancer cell lines of prostate (PC-3 and DU-145), breast (MDA-MB-231), lung (A549) and a normal breast epithelial cells (MCF10A) were executed by Sharma et al. Biological data indicated that A549 lung cancer cell line was most susceptible towards the test compounds. Among the test compounds, compound (200) exhibited encouraging cytotoxicity with IC50 value of 11.46 ± 1.46 µM on A549 lung cancer cell line as compared to the standard 5-FU (IC50 value of 30.47 ± 1.90 µM). It was also found that treatment of compound (200) on A549 lung cancer cell led to G2/M phase of cell cycle arrest and able to induce apoptosis [222]. Tay et al. developed novel 4-naphthyl-2-aminothiazole-containing compounds and screened them for their in vitro antimicrobial and anticancer activities. Some of the compounds showed remarkable antibacterial and antifungal activities. Anticancer and cytotoxic activities were carried out against human hepatocellular carcinoma Hep-G2 and human lung adenocarcinoma A549 cell lines while doxorubicin was used as reference drug with IC50 values 5 µM and 0.5 µM. Compounds (201a) and (201b) were determined as the most cytotoxic and anticancer potential compounds. Compound (201a) showed 66% cell viability IC50 values 200 µM for an incubation period of 24 h against Hep-G2 cell lines. Whereas, against adenocarcinoma cell lines (A549), only compound (201c) with 57% viability at 200 µM for 48 h was found as most potent anticancer agent [223]. A novel series of thiazoles bearing 1,3,4-thiadiazole scaffold was executed by Gomha et al. in order to screen for their in vitro anticancer activity against liver HEPG2 cancer cell line. Out of the test compounds, the compound (202) having ester group (CO2Et) at position 2 of the thiadiazole ring have shown superior antitumour activity (IC50; 0.82 µM) against liver carcinoma cell line (HEPG2) in comparison to the standard drug doxorubicin (IC50; 0.72 µM). However, some other compounds had also shown good antitumour activity against HEPG2. The SAR study revealed that presence of electron-withdrawing group at the position 2 and 4 in the aryl moiety enhances the activity and electron-donating groups such as methyl
71
or methoxy at the position 4 in the aryl moiety of the thiadiazole ring attributed to decrease in the cytotoxic activity [224]. Park et al. have screened 18 new imidazo[2,1-b]thiazole-containing compounds for their in vitro antiproliferative activities against A375P human melanoma cell line and NCI-60 cell line panel. Some of the test compounds exhibited superior activity against the cell lines used than the standard drug sorafenib. Out of test compounds, compounds (203a) and (203b) demonstrated higher potencies against A375P human melanoma cell line than sorafenib (IC50; 5.6 µM) with sub-micromolar IC50 values of 1.40 and 0.79 µM. Compounds (203a) and (203b) demonstrated high selectivity ratios of 4.25 and 4.14 against melanoma as compared to other cancer types. In silico ADME profiling results together with in vitro antiproliferative activities make compounds (203a) and (203b) promising leads for development of selective and potent agents for treatment of melanoma [225]. In an another study, Park et al. developed a new series of pyrimidinyl-imidazo[2,1-b]thiazolecontaining compounds and investigated their antiproliferative activity against A375 human melanoma cell line. Biological data revealed that all the compounds exhibited moderate antiproliferative activity against the cell line as compared to the standard drug sorafenib. Among the test compounds, the cyclic sulphonamide derivative (204) (IC50; 1.9 µM) demonstrated most potent antiproliferative activity as compared to sorafenib (IC50; 5.6 µM) [226]. Two series of novel 2-substituted 5,7-dihydroxyanthra[2,1-d]thiazol-6,11-diones of natural rhein were inspected by Liang et al. for their in vitro antitumour activities against A549 and HeLa human cancer cell lines. Some compounds were found to be more potent than rhein. Out of the test compounds, compound (205) bearing methyl piperazine moiety giving the IC50 of 5.4 µM and 4.3 µM, respectively, and was around 30 times more potent than rhein (IC50 115.1 µM & 123.2 µM, respectively) [227].
72
O
H N
O
N
N
HN H3C
NO2
CH3
Br
O
N
N
S
N
S
(198)
N
N
(199)
H3C N
S N
N
O
N NH O HN
O
N S
O
(200)
N
CH3
S
H N
O CH3
S N
N
N
O Compd. 201a;
N
R
(202)
N
Cl
S 202b;
(201)
N
F O
H2C 202c; S
Cl
R
HN N
S
O N
CH3
NH N
N N
N NH
N
N
R
HN OH
203a; 203b;
R H 2-OH
S
HO
N
S
(204)
N
O (203)
Compd.
HO
O
N
N
N CH3
O (205)
Figure 35: Thiazole derivatives as cytotoxic agents (198-205). In a study, Santos et al. reported 6,7-bis(hydroxymethyl)-1H,3H-pyrrolo[1,2-c]thiazoles for their anticancer activity targeting triple-negative breast cancer (MCF-7, HCC1954 and HCC1806 cell lines). Among all the test compounds, compounds (206) and (207a) was the most promising anti-proliferative agent against HCC1954 cancer cell lines with IC50 values of 0.3 µM and 0.6 µM, respectively. Against HCC1806 cell line, (207b) is the most promising compound with IC50 value of 5.4 µM. The SAR study revealed that presence of a hydroxyl phenyl group at C-3 seems to improve the anti-cancer activity for the TN cell line [228]. A series of novel p-toluenesulfonyl-hydrazinothiazoles and hydrazino-bis-thiazoles was prepared and screened for in vitro anticancer activity by Zaharia et al. Some of the 73
compounds were found to possess good anticancer activity against prostate DU-145 and hepatocarcinoma Hep-G2 cancer cell lines than the standard drug doxorubicin. Compounds (208a) (IC50; <5.65 µM on Hep-G2) and (208b) (IC50 of 4.68 µM on DU-145 and below 4.51 µM on Hep-G2) showed the best anticancer activities [229]. Shao et al. introduced novel ferrocenyl-containing thiazole-containing compounds and scrutinized them for their anticancer activity against three human cancer cell lines including HL-60 leukaemia, BGC-823 gastric carcinoma cells and Hep-2 laryngic carcinoma cells. Some compounds exhibited good anticancer activity at concentration of 10 µM. Ccompound (209) having methoxy substitution displayed most potent cytotoxic activities on HL-60 leukaemia, BGC-823 gastric carcinoma cells and Hep-2 laryngic carcinoma cells with 81.40, 63.41, and 53.11% inhibition, respectively at 10 µM [230]. Synthesis and anticancer activity of novel 2,6-disubstituted benzothiazole-containing compounds against three human cancer cell lines MCF-7, HeLa and MG63 have been accomplished by Sadhasivam et al. Out of the test compounds, sulfonamide derivative (210) demonstrated most potent cytotoxicity against MCF-7, HeLa and MG63 with IC50 values of 36, 44 and 34 µM, respectively in comparison to cisplatin (IC50; 3.5 µM). On the other hand, compound (211) also displayed cytotoxicity with IC50 range of 48 to 53 µM against all the cell lines [231]. Cytotoxic activity of new thiazolyl-pyrazoline derivatives against A549 human lung adenocarcinoma and NIH/3T3 mouse embryonic fibroblast cells was reported by Altintop et al. Among the test compounds, compound 2-[5-(4-fluorophenyl)-3-(5-chlorothiophen-2-yl)4,5-dihydro-1H-pyrazol-1-yl]-4-(4-bromophenyl)thiazole (212) was identified as most favourable anticancer agent against A549 cancer cells with an IC50 value of 62.5 µg/mL when compared with cisplatin (IC50; 45.88 µg/ml) and non-toxic potential against NIH/3T3 cells [232]. Several substituted 4-aryloxy- and 4-arylsulfanyl-phenyl-2-aminothiazoles were screened for their cytotoxicity activity against estrogen-positive, estrogen-negative, and adriamycinresistant human breast cancer cell lines by Gorczynski et al. Compounds (213a) & (213c) showed selectivity against T-47D (IC50; 0.917 & 0.54 µM, respectively), compound (213b) against MDA-MB-435 (IC50; 0.759 µM) were emerged as most potent cytotoxic compounds endowed with excellent inhibitory activities. From SAR viewpoint, it was found that electron 74
donating para-methyl substituent in compound (213c) showed increased efficacy over the electron-withdrawing para-chloro thiazole in compound (213a) [233]. Andreani et al. described synthesis and antitumour activity of 6-substituted imidazothiazole guanylhydrazones. All the compounds were subjected for their antitumour activity against NCI cell lines. Almost all the cell lines were found to be more sensitive towards 2-methylimidazothiazoles for which the antitumour activity was higher (214-216) with mean pGI50 values of 5.03-5.40 µM displaying lowest toxicity. Compound (217) was effective on growth and death of HL-60 leukaemia Cells (selectivity towards leukaemia Cells), induces apoptosis as well as causes mitochondrial disruption of ∆Ψm parameter [234]. In an another study, Andreani et al. reported new guanylhydrazones analogues of Imidazo[2,1-b]thiazoles for their antitumour activity at NCI cell lines. Among them, guanylhydrazone
of
2-chloro-6-(2,5-dimethoxy-4-nitrophenyl)imidazo[2,1-b]-thiazole-5-
carbaldehyde (218) have been emerged as most active compound exhibiting log GI50 values (panel/cell line): -5.81 (colon/COLO 205), -6.23 (ovarian/OVCAR-3), -5.84 (renal/RXF 393), and -5.72 (leukemia/K-562). Moreover the compound (218) was found to be an inhibitor of complex III of the mitochondrial respiratory chain and is able to induce apoptosis in the cell lines HT29 and HL60 [235]. Popsavin et al. synthesized two novel tiazofurin analogues starting from D-glucose and tested for their in-vitro antiproliferative activity. Analogues (219a) and (219b) exhibited potent cytotoxic activity against some human leukaemia and solid tumour cell lines, but none of them found to exhibit any significant cytotoxicity towards normal foetal lung MRC-5 cells. Remarkably, compound (219a) was found to be 570-fold more potent than tiazofurin against MCF-7 cells. Consequently, same analogue was also active against HeLa cells, but it was almost 2-fold less potent with respect to the parent molecule 33 while compound (219b) showed most powerful cytotoxicity against HL-60 and HeLa cells being almost 100-fold more active than tiazofurin [236].
75
HO
CH3
HO
HO
CH3
HO
N S
R
207a; 207b;
H OH
S
(206)
N
(207)
O S NH O HN
H3C
OH
N
Compd.
N
Compd.
S
R
H N
Fe
R
208a; 208b;
O
H COOCH2CH3
(209) H N
NH N
HN O (211)
F
O
S
+
N
H3N I-
Compd.
R
N
(213)
(212)
HN
NH N
H3C
N S
N
N S
N
H3C
S (215)
(214)
N
HN N HN N
NH
H3C
O CH3
O CH3
N
N
HN
H3C
CH3
S
H N
4-Cl 3,4-Cl2 4-CH3
O2N
S
H3C H H2N N
R
213a; 213b; 213c;
S
Br
S
NH2
CH3
N H
S
CH3 O
N N
O
N
(210)
Cl
OCH3
N HN
S
S O
N S
CH3
(208) O
N
S
NH N
H3C N
N
H3C S
(216)
N
N H
(217)
H2N HN
NH N N
Cl
S
CH3 O
HO
O N (218)
O
NO2 CH3
S N
HO
O
NHCOR NH2
Compd.
R
219a; 219b;
C6H11 C11H23
(219)
Figure 36: Thiazole derivatives as cytotoxic agents (206-219). A novel series of 1, 3-thiazole-benzofuran and 1, 3-thiazole-pyrazole-benzofuran derivatives was synthesized by Gomha et al. Some of the newly synthesized derivatives were tested for their in vitro cytotoxic activity against the human breast carcinoma (MCF-7) cell lines and compared with doxorubicin. Compound 4-Methyl-5-(p-tolyldiazenyl)-2-(2-(1-(4, 6, 7-
76
trimethoxybenzofuran-5-yl) ethylidene) hydrazinyl) thiazole (220) appeared to be a potent cytotoxic agent (IC50; 0.69 µM). From SAR viewpoint, introduction of electron-donating group (methyl) at C4 of the phenyl group at position 5 in the 1, 3-thiazole ring improves the antitumour activity [237]. A new facile synthesis of heterocycles containing thiazole and 1, 3, 4-thiadiazole or two thiazole rings was introduced by Gomha et al. These compounds were subjected for their in vitro anticancer activity against hepatocellular carcinoma cell line (HepG-2). Among the test compounds, the best results were obtained in compounds (221) (IC50; 1.61 ± 1.92 µg/ml) and (222) (IC50; 1.98 ± 1.22 µg/ml). SAR study concluded that thiazole ring and 4-CH3-Ph are essential for anticancer activity in most potent compound (221). Furthermore, presence of the N-phenylcarboxamide group in compound (222) also enhances the activity [238]. Dos Santos Silva et al. have synthesized hybrids of pyridyl and 1,3-thiazole moieties and screened against HL-60 (leukemia), MCF-7 (breast adenocarcinoma), HEPG2 (hepatocellular carcinoma), NCI-H292 (lung carcinoma) human tumour cell lines and non-tumour cells (PBMC, human peripheral blood mononuclear cells). Among all the test compounds, compound (223a) and compound (223b) presented cytotoxic activity and most favourable selectivity index in all tumour cell lines, including HEPG2 (IC50; 2.2 and 5.6 µM, respectively). Further, these compounds produced their cytotoxic effect without causing toxicity to normal cells (PBMC) (IC50 > 30 µM) with a most favorable selectivity index [239]. Cytotoxic activity of a series of new quinoline-thiazole based azo compounds against MCF-7 (human breast cancer cell line) and K562 (CML cell line) was reported by Sarangi et al. The results of in vitro cytotoxic activity of the synthesized compounds has revealed that the compound 4-(((Z)-(2-chloroquinolin-3-yl) (4-phenylthiazol-2-ylimino) methyl) diazenyl)benzenesulfonic acid (224) showed excellent cytotoxic action against MCF-7 & K562 cancer cell lines (IC50; 15.96 & 13.05 µM, respectively) [240]. Since androgen receptor (AR) plays a stimulator role in many different prostate cancer cell types during cancer, targeting androgen receptor -DNA-binding domain (AR-DBD) some novel thiazole-based derivatives were introduced by Xu et al. Among the test compounds, only compound (225) containing a methylketone moiety have shown inhibitory effect on human prostate cancer cell line LNCaP/AR with IC50 value of 0.38 µM without significant antiproliferative effects on other cell lines PC-3 (AR-negative), SW620, MCF-7 (ER77
positive), and L-O2 (non-cancerous). SAR study revealed that reducing the methylketone in (225) to alcohol significantly reduced the activity [241]. Some new thiazole, pyridinone, thiophene, chromene and pyrazole derivatives containing biologically active acetanilide nucleus were synthesized by Abdel-Latif et al. In vitro cytotoxic activity of the synthesized heterocyclic scaffolds was assessed against human breast cancer cell line (MCF-7) and compared with 5-fluorouracil. Among all the screened thiazolecontaining compounds, compounds (226) & (227) exhibited significant cytotoxic activity (IC50; 6.9 & 9.3 µg/ml, respectively) as compared to 5-fluorouracil (IC50; 5.5 µg/ml) [242]. Some novel thiophene, thiazole and coumarin based on benzimidazole derivatives were developed by Mohareb et al. and screened for their in vitro their cytotoxicity and toxicity. Cytotoxic activity was carried out against human lung carcinoma (A549), lung cancer (H460), human colorectal (HT29), gastric cancer cell (MKN-45), glioma cell line (U87MG) and cellosaurus cell line (SMMC-7721) using foretinib as standard reference. Among the tested thiazole-containing compounds, derivatives (228a) (IC50; 0.25-3.28 µM) & (228b) (IC50; 0.23-0.82 µM). Whereas, compound (228b) was found to possess non-toxicity against shrimp larvae indicated that compound may provide a suitable lead molecule in cancer treatment [243]. A new series of thiazole, thiadiazole and oxadiazole based1,4-dihydropyridine derivatives was synthesized by Ahmed et al. In vitro cytotoxic activity of newly synthesized compounds was preformed against liver (HEPG2), cervical (HeLa), and breast (MCF-7) cancer cell lines, while doxorubicin was used as standard. Among the tested thiazole compounds, compounds (229a) and (229b) exhibited highest toxicity against cervical (HeLa) and breast (MCF-7) cancer cell lines (IC50; 2 nM & 3 nM, respectively) as compared to doxorubicin (IC50; 5 nM & 2 nM, respectively). SAR studies revealed that both (229a) and (229b) compounds with electron withdrawing groups 4-Cl-Ph exhibited significantly higher activity than those of compounds containing an electron withdrawing group 4-NO2-Ph [244]. In vitro antitumour activity of a new series of 1,4-bis(1-(5-(aryldiazenyl)thiazol-2-yl)-5(thiophen-2-yl)-4,5-dihydro-1Hpyrazol-3-yl)benzene derivatives was performed by Gomha et al. Anticancer activity was done against hepatocellular carcinoma (HEPG2) cell line, using doxorubicin as a reference drug (IC50; 0.72 ± 0.18). The results revealed that compound (230) exhibited most potent anticancer activity (IC50; 1.37 ± 0.15) against hepatocellular carcinoma (HEPG2) cell line than the standard drug. From SAR study revealed that substituent at 78
position 4 in the thiazole ring and introduction of a thienyl ring in compound (230) affect the in vitro anticancer activity, while electron-withdrawing group follows the order of activity as; nitro > chlorine > bromine at the para position of the phenyl group attached to thiazole ring enhances the antitumour activity [245]. Two series of 2-aminothiazole and isoquinoline fused naphthalimide derivatives were prepared and screened for their anticancer activity against hepatocellular carcinoma by Ge et al. Among the tested thiazole fused naphthalimide derivatives, derivative (231a) exhibited maximum potency against hepatocellular carcinoma (SMMC-7721, HEPG2, HCT-116, and K562) with IC50; 1.61± 0.13, 4.67± 0.31, 3.81± 0.25, and 12.41± 1.56, respectively. Further, compound (231a) caused acute toxicity in tumour transplant models: solid tumour (tumour growth inhibition evaluation) and pulmonary metastasis tumour (tumour metastasis evaluation) against mice hepatoma cell line. However, compound (231b) exerted potent effects against these models with no toxicity. Compound (231b) exerted maximum inhibition against cancerous liver cell growth mainly by G2/M phase arrest by the up-regulation of cyclin B1, CDK1 and p21 [246]. Antibacterial and cytotoxic activities of 2-(3’-Indolyl)-N-arylthiazole-4-carboxamide derivatives were described by Tanak et al. In vitro cytotoxicity was done against a panel human cancer cell lines using doxorubicin as standard (IC50; 0.45-7.65 µM). Among the tested thiazole carboxamide derivatives, derivative (232a) (IC50; 8.64 µM against HEK293T) and (232b) (IC50; 3.41 µM against HeLa) were identified as the most potent compounds as compared to the standard drug. The preliminary mechanism of action studies indicated that thiazole carboxamide (232a) was crucial for selectivity and cytotoxicity against HeLa cells via induction of cell death by apoptosis [247].
79
CH3 O N NH S O N CH3 O
N
H3C
N H3C
CH3
CH3
N N
N HN
H3C O HN CH3
N
O
S
S
O
N
CH3
N
(220) (221)
O NH N
S
O S
N
N
N H
N
H N
N
N
(222) Cl
N
N N
O OH S O
N H
(225) H N
S
N
N H
CH3
N O R
NO2
CH3
S
NH N
H3C
NH O
(228)
CH3 OCH2CH3
NH
S
N
N
N
N
S R (229)
229a; 229b;
N
228a; 228b;
H3C
Compd.
N
Compd.
(227)
(226)
O
N CH3
N
R
S
S N
O
CH3
O
O O
CH3 H
O
N
O
NH
N
N
H3C
N
R
223a; 223b;
S
O
N
CH3
Compd.
(223)
S
(224)
Cl
S
CH3
S N N
R Cl NO2 O2N
N N S
N
N
N
CH3 S (230)
Figure 37: Thiazole derivatives as cytotoxic agents (220-230). Synthesis of a new series of coumarin substituted thiazolyl-3-aryl-pyrazole-4-carbaldehydes and in vitro cytotoxic activity against MCF-7, DU-145 and HeLa cell lines was reported by Vaarla et al. Out of the test compounds, compounds (233a) against HeLa (IC50; 5.75 µM) and (233b) against HeLa cells and DU-145 cell (IC50; 6.25 µM, 10.81 µM, respectively) 80
exhibited significant cytotoxic activity as compared to the standard drug doxorubicin (IC50; 2.49-3.92 µM). Hence, it can be concluded that presence of pharmacologically active moieties like coumarin, thiazole and pyrazole along with a potential functional group like aldehyde in their structures does contributes to potential cytotoxic activities [248].
R
H N
O
CH3 O
H N
S O
N
O
.nHCl
H3C
N
O
S
O H3C
N H
NH2
CH3
O
N (232) (231) Compd. Compd. 231a; 231b;
R
R1
R2
n
CH2CH2NH2 H
232a; 232b;
4 3
OCH3 F
3,4,5-(OCH3)3 4-OCH3
CH3 O
O
Compd.
R N
N N
O
233a; 233b;
R 6,8-Cl2 6,8-Br2
S (233)
Figure 38: Thiazole derivatives as cytotoxic agents (231-233). 3
An insight view of recent patents filed on thiazole-containing compounds as anticancer agents The main objectives of this section is to deals with the patents filed on thiazole-containing compounds reported in international patents from all companies (Given under the section 3.1; Table 2). Thiazole is a well-known and important sulphur and nitrogen containing fivemembered heterocyclic compound. Thiazole occurs in nature and numbers of scientist have carefully revised various methods for synthesis of thiazole [249]. In past two decades, a lot of derivatives containing thiazole ring system have been developed to find a new drug that works in plethora of cancer with fewer side effects. The present review gives an account of the recent therapeutic patent filed on applications of selected thiazole-containing compounds working in cancer treatment. Findings revealed that, a vast variety of patents have been
81
registered in last two decades on thiazole-containing compounds which has drawn their utmost attention due to target specific anticancer activity. Thus, thiazoles have found their prominent role in order to develop more effective and clinically interesting anticancer agents.
3.1
Table 2 List of some patents related to anticancer activity of thiazole [250-278]. S.No. 1.
Date Nov 25, 2015
Patent no. CN105078977 A
Invention disclosed Application of 5-(2-nitro ethyl) thiazole derivatives as anticancer drug.
Ref. [250]
2.
Oct 1,2015
US20150274714 A1
[251]
3.
Feb 5, 2015
WO2015016442 A1
4.
Mar. 25, 2014
US 8680103 B2
Anti-invasion, anti-migration and thiazole analogs for treatment of cellular proliferative disease. Novel phenylthiazole-based hydroxamic acid and anti-cancer composition containing active ingredient. Preparation of 2-aminothiazole-5-aromatic carboxamides as kinase inhibitors.
5.
Aug. 5, 2014
US 8796298 B2
[254]
6.
Jul 22, 2014
US8785444 B2
Combination of a B-Raf inhibitor: N-{3-[5(2-amino-4-pyrimidinyl)-2-(1,1-dimethyl ethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}2,6difluorobenzene sulfonamide and the Akt inhibitor: N-{(1s)-2-amino-1-[(3fluorophenyl)methyl]ethyl}-5-chioro-4-(4chioro-1-methyl-1H-pyrazol-5-yl)-2-10 thiophenecarboxamide useful in the treatment of cancer. Thiazoles and pyrazoles valuable as kinase inhibitors.
7.
Jul. 18, 2013
US 2013/0184280 Substituted thiazole derivatives as VEGFR2 A1 kinase inhibitors.
[256]
8.
Dec. 19, 2013
[257]
9.
Mar. 12, 2013
US 2013/0338201 A method of cancer management with 2-(1HA1 indole-3-carbonyl)-thiazole-4 carboxylic acid methyl ester. US 8394960 B2 Thiazole carboxamide derivatives and their use to treat cancer.
10.
Mar. 26, 2013
US 8404691 B2
[259]
11.
Feb. 21,2012
US 8119812 B2
Imidazothiazole derivatives having a proline ring structure having anti-tumor activity by inhibition of murine double minute 2 (Mdm2) or their salt. The novel invention inhibited the CDC7 protein kinase activity, and control of cell proliferation.
[252]
[253]
[255]
[258]
[260]
82
12.
Apr. 12, 2012
US 2012/0088759 Thiazole derivatives as orexin receptor A1 antagonists.
[261]
13.
28.Aug. 2012
US8252822 B2
[262]
14.
Sep. 18, 2012.
US 8268811 B2
Imidazothiazole-chalcone derivatives as potential heterocyclic compounds and their anticancer agents. Thiazoles and pyrazoles useful as kinase inhibitors.
15.
Aug. 04,2011 Mar. 10, 2011 Jun. 15, 2010 Feb 16,2010
US 2010190299 A1 US 2011/0060013 A1 US 7737134 B2
[264]
Feb. 17, 2009 Oct 23,2008
US 7491725 B2
Feb. 5, 2008 Feb. 15,2007
US 7326727 B2
23.
Oct. 2, 2007
US 7276602 B2
Novel thiazole derivatives having a CDC7 inhibitory action. Thiazoles and pyrazoles useful as kinase inhibitors. Thiazole derivatives as anticancer agents and their use. Selective anti-cancer agents; Thiazolidinones amides, thiazolidine carboxylic acidamides, and serine amides including polyamine conjugates Development of 2-aminothiazole-5-aromatic carboxamides as kinase inhibitors. Use of compounds for the preparation of pharmaceutical compositions for the treatment of pathologies in which inhibition of the interaction between HIF-1α and p300 is beneficial, in particular as antiangiogenic medicaments for the therapy of solid tumors. Novel furanthiazole derivatives which are useful as inhibitors of heparanase. Thiazole derivatives and their production and uses as pharmaceutical agents as inhibitors of polo kinases in cancer, auto-immune diseases, cardiovascular diseases. Novel isothiazole derivatives that is useful in the treatment of hyperproliferative diseases.
24.
Apr 13,2006
US 0079503 A1
25.
Jan. 20, 2005.
26.
Mar. 16, 2004
US 6706718 B2
Novel 3-(2,4 dimethylthiazol-5-yl)indeno[1,2- [275] c]pyrazol-4-one derivatives which are useful as cyclin dependent kinase (Cdk)inhibitors.
27.
Apr. 10, 2001
US 6214851 B1
N-Adamant-1-yl-N1-[4-chlorobenzothiazol-2- [276] y1] urea useful in the treatment of inflammation and as an anticancer radiosensitizing agent.
16. 17. 18.
19. 20.
21. 22.
US 7662842 B2
US 20080261980 A1
US0037862 A1
Thiazoles and their production and uses as pharmaceutical agents as inhibitors of polo kinases in cancer, auto-immune diseases, cardiovascular diseases. US 2005/0014767 Benzimidazole, benzoxazole,and A1 benzothiazole derivatives for the treatment of cancer and other diseases.
[263]
[265] [266] [267]
[268] [269]
[270] [271]
[272] [273]
[274]
83
4
28.
Apr 26, 2016
US9321777 B2
6-Triazolopyridazine sulfanyl benzothiazole derivatives as met inhibitors.
[277]
29.
Feb-112016
US 20160038472 A1
Agent for the prophylaxis and/or treatment of neoplastic diseases.
[278]
Novel thiazole-containing cyclic peptides as anticancer agents Peptide-based chemotherapies are currently being used to treat cancer. These cyclic peptides offers unique advantages such as low molecular weights, the ability to specifically target tumour cells, and low toxicity in normal tissues [279]. Current research emphasized on developing such peptide derivatives that can assist as cancer targeting moieties and permeabilize membranes with eventually cytotoxic impacts. Considerably, the challenge lies in the development of the clinical application of therapeutic peptides. Some properties like improved delivery to tumours, minimized non-specific toxic effects and discerning pharmacokinetic properties are highly warranted to produce a powerful therapeutic peptide for cancer treatment [280]. In this review, we will survey some thiazole based modified cyclic peptide antibiotic and their applications in cancer treatment.
4.1
Berninamycin Berninamycin is a highly modified cyclic peptide antibiotic produced by Streptomyces bernensis. It contains two oxazole rings together with a novel pyridothiazolopyridinium chromophore, ‘berninamycinic acid. Berninamycin is known to be a potent inhibitor of protein synthesis in Gram-positive bacteria and, in bacterial extracts, it inhibits the synthesis of polypeptides in response to homopolynucleotide ‘messengers’ or phage RNA [281].
84
O
H N
O
CH2 NH2
N H CH 2 N
O
O N
O
N
S
N H
O
O
NH NH
O
H3C
N O
H3C HN H3C O
HN N
CH2 O CH3
O HN
H3C O
O
HN H3C
OH
Figure 39: Berninamycin Isolation and identification of berninamycin A: The culture of S. atroolivaceus using ISP2 agar medium was extracted by acetone and the acetone extract was filtered and concentrated to aqueous residue by the rotary evaporator. The acetone extract was subjected to open column chromatography using hydrophobic resin eluted with 20% MeOH, 60% MeOH, and MeOH. Berninamycin A was isolated by repeatedly subjecting MeOH fraction to preparative HPLC. The identification of berninamycin A was accomplished by the combination of MS and NMR spectrum data. The High Resolution ESI-MS spectrum data determine the molecular formula C51H51N15O15S [282].
4.2
Micrococcin Micrococcin and micrococcin P are produced, respectively, by a bacterium related to Micrococcus varians and by Bucilluspumilis and it is now clear that these two antibiotics are identical. Micrococcin contains several thiazole rings. Micrococcin exert effects upon protein synthesis both in intact gram-positive bacteria and in prokaryotic cell extracts in general [283]. Micrococcin P1 is known to have powerful anticancer activity. Antibacterial activity of micrococcin P1 is attributed to inhibition of elongation factor G (EF-G) and initiation factor 2 (IF2) that prevent the binding of EF-G to the ribosome [282]. 85
CH3
O S
N H
N N
S
H N O H H3C
S
O
OH
S
N
O H3C
HO
S
HO
N
CH3 O
N
S
CH3 O
S
HN
HN
N NH H N
HO O
H3C
S H CH 3
H3C
CH3
HO
O
of
HN
H3C
as
anticancer
O
N
O
S
micrococcin
H N
O
N
S
N
NH
CH3
HN
CH3
S
Figure 41: Micrococcin P2
Figure 40: Micrococcin P1 Patent
O
N
N S
H N
N H
N
N
N
CH3
O
agents
and
method
for
diagnosing
cancer (WO2002102400 A1) A use of the macrocyclic peptide compound micrococcin as anticancer agents which exhibit selective toxicity against cancer cells. When the compounds micrococcin is treated to cancer cells and normal cells, they exhibit selective toxicity only against cancer cells to induce apoptosis of the cancer cells. The anticancer agent comprising at least one compound selected from the group consisting of the macrocyclic peptide compound micrococcin as an active ingredient, did not show toxicity against normal cells, but showed selective toxicity against cancer cells, thereby inducing selective apoptosis of cancer cells. Therefore, the macrocyclic peptide compounds micrococcin is useful as anticancer agents [284]. 4.3
Thiocillin I Thiocillins had been isolated from other strains of B. cereus, they had never been isolated from B. cereus ATCC 14579. To test whether B. cereus ATCC 14579 produces the thiocillins, assayed the extracts from its cell material and cell-free culture fluid by liquid chromatography (LC)/MS [285].
86
CH3
O S
S
H N H O H3C
N H
N N
OH
N N N
S
HO H
CH3 H O
S HN
O H3C HO
H
S
N
NH
H
HN
NH O
OH
HH3C O
N H3C
CH3
S
Figure 42: Thiocillin I Anticancer profile thiopeptides One of the biological properties of thiopeptides of major interest, apart from the antibacterial one, is anticancer activity. In this regard, thiostrepton was found to selectively kill cancer cells without showing any cytotoxicity against healthy tissues. Such a promising effect has been demonstrated to arise from selective inhibition of transcription factor forkhead box M1 (FOXM1). FOXM1 overexpression is associated with the development and progression of cancer and its selective targeting is a very large achievement, as transcription factors have been considered undruggable for a long time [286]. O
S
H3C NH
S
O
HO
NH NH CH3
O
N
H2N CH3
O
HN OH
O H N
N S
CH2
O
O
O
NH
CH3
O N
N O H3C HO
CH2
O S
HN NH
N
S O
H3C
N
N
H N
HO
CH2
NH O
H H3C H3C
87
Figure 43: Thiostrepton Patent on cancer therapeutic agent comprising thiopeptide with multiple thiazole rings (WO 2002066046 A1): This invention relates to cancer therapeutic agent comprising thiopeptide with multiple thiazole rings, its derivative or its pharmaceutically acceptable salt as an effective ingredient [287]. Since cancer cells show higher protein synthesis rate than that of normal cells, the protein synthesis inhibitor can show cancer therapeutic effects with selective toxicity against cancer cells. As for procaryotes, kanamycm, tetracyclme, chloramphenicol, erythromycin, streptomycin, lincomycm, clindamycin, thiostrepton and micrococcm are used as antibiotics inhibiting protein synthesis. Thiopeptide and its derivative of the present invention is preferably selected from a group consisting of compounds represented by formula 1 to formula 15, thiostrepton, micrococcin P, nosiheptide, siomycin, sporangiomycin, althiomycin, Promoinducin, Berninamycin, glycothiohexide alpha, Sch40832, GE37468A, GE37468B, GE37468C, GE2270, GE2270 factors C2a, GE2270 factors D2, GE2270 factors E, thiocillins, thiopeptin, amythiamicin A, sulfomycin, Thioxamycin and MJ3471F4A. Thiopeptide and its derivative of the present invention show useful effects as a cancer therapeutic agent by inducing apoptosis of cancer cells. Cancer therapeutic effect is confirmed by showing selective toxicity against cancer cells, when cancer cells and normal cells were treated with thiopeptide and its derivative of the present invention dissolved in a pharmaceutically acceptable solvent, such as dimethyl sulfoxide. Cancers, wherein thiopeptide and its derivative of the present invention can be applied, can be selected from a group consisting of gastric cancer, liver cancer, colon cancer, lung cancer, cervical cancer, breast cancer, ovarian cancer and leukemia. Particularly, thiopeptide and its derivative of the present invention can be effectively applied, but is not limited, to gastric cancer and liver cancer. In addition, it can be effectively applied to any known cancer. The IC50 value of thiopeptide and its derivative of the present invention against cancer cells range from 0.2 µmol to 12 µmol (Table 3). According to the present invention, a pharmaceutical composition containing thiopeptide with multiple thiazole rings and its derivative as an effective ingredient can be prepared by 88
mixing thiopeptide with multiple thiazole rings and its derivative with a pharmaceutically acceptable carrier [288]. 4.4
Table 3 Derivatives against various cancer cell line IC50; µM. Thiopeptide and
its Gastric cancer
derivatives
5
Liver Cancer
SNU- MKN-
SNU-
AGS
HEP
HEP 3B
638
74
216
Thiostrepton
0.30
4.2
0.41
0.4
0.71
0.82
0.74
Micrococcin P1
0.41
7.3
0.44
0.5
0.91
0.94
0.83
Siomycin A
0.91
6.21
0.75
0.71
1.3
1.9
1.6
Bernianamycin A
0.75
2.43
0.88
0.99
1.3
1.04
0.99
Althomycin
0.77
7.13
0.77
0.85
1.43
0.88
0.81
Thiocillin 1
0.99
11
7.5
1.43
1.34
2.34
2.12
G2
SKHEP-1
Conclusion and future aspects The current review emphasizes on new horizons of anticancer potential of thiazole based heterocyclic derivatives. Structural activity relationship studies and biological activity data of thiazoles establish them as possible multi-target enzyme inhibitors depicting their pharmacological potential through inhibition of some metabolic pathways. An increasing numbers of patents granted on thiazole-containing compounds and their exploration for possible clinical use in ongoing research and development reveal the potential of these derivatives in medicinal chemistry. Thus, it is clear from above that thiazole scaffold bearing compounds present plethora of applications in drug development for treatment against a variety of cancers. Despite remarkable advancements of thiazole-containing compounds, still some concerted research endeavors are requisite; •
Development of suitable synthesis protocols through application of green chemistry to provide a strong driving force for the future thiazole-containing compounds development.
89
•
The detailed elucidation of biological activity through investigation of mode of action especially on laboratory animals followed by clinical studies for the potent compounds.
•
A detailed study on pharmacodynamic and pharmacokinetic properties of listed potent compounds for anticancer activities.
•
Another attractive aspect is to work on identification and isolation of naturally occurring thiazole-containing compounds and antibiotics from plant and marine sources.
Since it is evident from this review that thiazole based compounds may be useful as inhibitors of multiple enzyme target inhibitors or some other metabolic pathways. Thorough investigation on adverse effects associated with thiazole-containing compounds can be a prospective area for scientific research. Development of superior analogs with better efficacy and pharmacokinetics and less side effects would be incredible contribution for the betterment of human beings. Conflict of interest Authors declare no conflict of interest. The authors alone are responsible for the content and writing of the paper. Acknowledgements Science and Engineering Research Board-Department of Science and Technology (SERBDST), Govt. of India is duly acknowledged for financial assistance under Fast Tract Scheme For Young Scientist (to Dr. Prabodh Chander Sharma) vide file No.: SB/FT/CS-134/2012 dated: July 15, 2014. Abbreviations: DNA
Deoxyribonucleic acid
LD50
cRNA
Complementary ribonucleic acid
NCI
lethal dose of a material that kill half of the sample population National Cancer Institute
IMP
Integral membrane protein
SAR
Structure activity relationship
B-RAF
Human gene that encodes a protein B-RAF
CNS
Central Nervous System
Bcr-Abl
Breakpoint cluster region proteinAbelson murine leukemia viral
TNF-α
Tumour Necrosis Factor receptor superfamily 90
oncogene EGFR
Epidermal growth factor receptor
µg/ml
Microgram per millilitre
TNBC
Triple-negative breast cancer
CA
Carbonic Anhydrase
MCF-7
Human breast cancer cell line
DPPH
HER-2
Human Epidermal Growth Factor Receptor 2
PI3K
2,2-Diphenyl-1picrylhydrazyl Phosphatidylinositol-4,5bisphosphate 3-kinase
MDAMB-468
A breast cancer cell line
P110α
IC50
Half maximal inhibitory concentration
RCC
EC50
Half maximal effective concentration
mTOR
CC50
50% cytotoxic concentration
VEGF
GI50
the concentration for 50% of maximal inhibition of cell proliferation
CAM
TGI50
concentration causing 0% growth inhibition
CDC
Complement Dependent Cytotoxicity
µg
Microgram
NF-ҡB
µM
Micromolar
Cdk
Protein complex (nuclear factor kappa-light-chainenhancer of activated B cells) Cyclin-dependent kinases
nM
Nanomolar
IR
Infrared
TGF-β
Transforming growth factor beta
NMR
Nuclear magnetic resonance
ALK
Anaplastic lymphoma kinase
IMP
integral membrane protein
Cys-751
Cysteine-751
IMPDH
Inosine 5'-monophosphate dehydrogenase
AIs
Aromatase inhibitors
NAD
Nicotinamide adenine dinucleotide
HAT
Histone acetylase
TAD
Topologically associating domains
HDAC
Histone deacetylase
Src-Abi
Oncogene; tyrosine kinase
SAHA
Suberoylanilide Hydroxamic Acid
CA-4
Combrestatin A-4
SMART
A new "smart" pill for advanced breast and bowel cancer
CA
Carbonic anhydrase
µmol/l
Micromole per liter
Kcal/mol Kilocalorie/mole
Phosphatidylinositol-4,5bisphosphate 3-kinase, catalytic subunit alpha Renal cell carcinoma Mechanistic target of rapamycin vascular endothelial growth factor Cell adhesion molecules
91
DMPM
Diffuse malignant peritoneal mesothelioma
∆Ψm
Mitochondrial membrane potential
References
[1]
B.G. Katzung, Basic & Clinical Pharmacology, 9th ed., Section VIII. Chemotherapeutic Drugs-Chapter 55. Published by Lange Medical Books, December 15th 2003, pp. 1276.
[2]
H.P. Rang, M.M Dale, J.M. Ritter, R.J. Flower, Rang and Dale’s Textbook of Pharmacology 6th ed., pp-718.
[3]
R. Majeed, A. Hamid, Y. Qurishi, A. K. Qazi, A. Hussain, M. Ahmed, R.A. Najar, J.A. Bhat, S.K. Singh, A.K. Saxena, Therapeutic targeting of cancer cell metabolism: role of metabolic enzymes, oncogenes and tumor suppressor genes, J. Cancer Sci. Ther. 4(9) (2012) 281-291.
[4]
L. Li, X. Zhou, W. Ching, P. Wang, Predicting enzyme targets for cancer drugs by profiling human metabolic reactions in NCI-60 cell lines, BMC Bioinformatics 11 (2010) 501.
[5]
R. Majeed, A. Hamid, Y. Qurishi, A.K. Qazi, A. Hussain, M. Ahmed, R.A. Najar, J.A. Bhat, S.K. Singh, A.K. Saxena, Therapeutic targeting of cancer cell metabolism: role of metabolic enzymes, oncogenes and tumor suppressor genes. J. Cancer Sci. Ther. 4(9) (2012) 281-291.
[6]
S. Kumar, M.K. Ahmad, M. Waseem, A.K. Pandey, Drug targets for cancer treatment: An overview, Med. Chem. 5(3) (2015) 115-123.
[7]
S.J. Conley, E. Gheordunescu, P. Kakarala, B. Newman, H. Korkaya, A.N. Heath, S.G. Clouthier, M.S. Wicha, Antiangiogenic agents increase breast cancer stem cells via the generation of tumour hypoxia, PNAS. 109(8) (2012) 2784-2789.
[8]
A.A.Vander Veldt, M. Lubberink, I. Bahce, M. Walraven, M.P. de Boer, H.N. Greuter, N.H. Hendrikse, J. Eriksson, A.D. Windhorst, P.E. Postmus, H.M. Verheul, E.H. Serne, A.A. Lammertsma, E.F. Smit, Rapid decrease in delivery of chemotherapy to tumours after anti-VEGF therapy: Implications for scheduling of anti-angiogenic drugs, Cancer Cell 21 (2012) 82-91.
[9]
H. Zahreddine, K.L. Borden, Mechanisms and insights into drug resistance in cancer, Front Pharmacol. 4 (2013) 1-8.
92
[10]
American
cancer
society.
Cancer
facts
and
figures
2018,
[https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and annual-cancer-facts-and-figures/2018/cancer-facts-and-figures-2018.pdf]
pp
1-76.
statistics/ (accessed
on
January 25, 2018). [11]
R. Scatena, P. Bottoni, A. Pontoglio, L. Mastrototaro, B. Giardina, Glycolytic enzyme inhibitors in cancer treatment, Expert Opin. Investig. Drugs 17(10) (2008) 1533-1545.
[12]
M.T. Chhabria, S. Patel, P. Modi, P.S. Brahmkshatriya, Thiazole: A review on chemistry, synthesis and therapeutic importance of its derivatives, Curr. Top. Med. Chem. 16(26) (2016) 2841-2862.
[13]
A.K. Jain, A. Vaidya, V. Ravichandran, S.K. Kashaw, R.K. Agrawal, Recent developments and biological activities of thiazolidinone derivatives: A review, Bioorg. Med. Chem. 20(11) (2012) 378-395.
[14]
M.V. Putz, C. Duda-Seiman, D. Duda-Seiman, A. Putz, I. Alexandrescu, M. Mernea, S. Avram, Chemical structure-biological activity models for pharmacophores’ 3Dinteractions, Int. J. Mol. Sci. 17 (2016) 1-23.
[15]
P.C. Sharma, K.K. Bansal, A. Deep, M. Pathak, Benzothiazole derivatives as potential anti-infective agents, Curr. Top. Med. Chem. 17(2) (2017) 208-237.
[16]
P.C. Sharma, A. Saini, K.K. Bansal, Synthesis of some thiazole clubbed heterocycles as possible antimicrobial and anthelmintic agents, Indian J. Heterocycl. Chem. 25(3-4) (2016) 303-310.
[17]
A. Ayati, S. Emami, A. Asadipour, A. Shafiee, A. Foroumadi, Recent applications of 1,3thiazole core structure in the identification of new lead compounds and drug discovery, Eur. J. Med. Chem. 97 (2015) 699-718.
[18]
P.C. Sharma, A. Jain, M. Shahar Yar, R. Pahwa, J. Singh, P. Chanalia, Novel fluoroquinolone
derivatives
bearing
N-thiomide
linkage
with
6-substituted-2-
aminobenzothiazoles: Synthesis and antibacterial evaluation, Arab. J. Chem. 10 (2017) S568-S575. [19]
B. Ghasemi, G. Sanjarani, Z. Sanjarani, H. Majidiani, Evaluation of anti-bacterial effects of some novel thiazole and imidazole derivatives against some pathogenic bacteria, Iran. J. Microbiol. 7(5) (2015) 281-286.
[20]
S. Khabnadideh, Z. Rezaei, K. Pakshir, K. Zomorodian, N. Ghafari, Synthesis and antifungal activity of benzimidazole, benzotriazole and aminothiazole derivatives, Res. Pharm. Sci. 7(2) (2012) 65-72.
93
[21]
J.M. Bueno, M. Carda, B. Crespo, A.C.Cunat, C. de Cozar, M.L.Leon, J.A. Marco, N. Roda, J.F. Sanz-Cervera, Design, synthesis and antimalarial evaluation of novel thiazole derivatives, Bioorg. Med. Chem. Lett. 26(16) (2016) 3938-3944.
[22]
A. Andreani, M. Granaiola, A. Leoni, A. Locatelli, R. Morigi, M. Rambaldi, Synthesis and antitubercular activity of imidazo[2,1-b]thiazoles, Eur. J. Med. Chem. 36(9) (2001) 743746.
[23]
K.W. Dawood, T.M. Eldebss, H.S. El-Zahabi, M.H. Yousef, Synthesis and antiviral activity of some new bis-1,3-thiazole derivatives, Eur. J. Med. Chem. 18(102) (2015) 266276.
[24]
R.N. Sharma, F.P. Xavier, K.K. Vasu, S.C. Chaturvedi, S.S. Pancholi, Synthesis of 4benzyl-1, 3-thiazole derivatives as potential anti-inflammatory agents: an analogue-based drug design approach, J. Enzyme Inhib. Med. Chem. 24(3) (2009) 890-897.
[25]
O. Bozdag-Dundar, M. Ceylan-Unlusoy, E.J. Verspohl, R. Ertan, Synthesis and antidiabetic activity of novel 2,4-thiazolidinedione derivatives containing a thiazole ring, ARZNEIMITTELFORSCH. 56(9) (2006) 621-625.
[26]
R.J. Weikert, S. Bingham Jr, M.A. Emanuel, E.B. Fraser-Smith, D.G. Loughhead, P.H. Nelson, A.L. Poulton, Synthesis and anthelmintic activity of 3'-benzoylurea derivatives of 6-phenyl-2,3,5,6-tetrahydroimidazo[2,1-b]thiazole, J. Med. Chem. 34(5) (1991) 16301633.
[27]
H. Ucar, K. Van derpoorten, S. Cacciaguerra, S. Spampinato, J.P. Stables, P. Depovere, M. Isa, B. Masereel, J. Delarge, J.H. Poupaert, Synthesis and anticonvulsant activity of 2(3H)-benzoxazolone and 2(3H)-benzothiazolone derivatives, J. Med. Chem. 41(7) (1998) 1138-1145.
[28]
B.Z. Kurt, I. Gazioglu, F. Sonmez, M. Kucukislamoglu, Synthesis, antioxidant and anticholinesterase activities of novel coumarylthiazole derivatives, Bioorg. Chem. 59 (2015) 80-90.
[29]
A. Lozynskyi, B. Zimenkovsky, R. Lesyk, Synthesis and anticancer activity of new thiopyrano [2, 3-d] thiazoles based on cinnamic acid amides, Sci. Pharm. 82(4) (2014) 723-733.
[30]
A.M. Omar, N.H. Eshba, Synthesis and biological evaluation of new 2,3-dihydrothiazole derivatives for antimicrobial, antihypertensive, and anticonvulsant activities, J. Pharm. Sci. 73(8) (1984) 1166-1168.
[31]
P. Franchetti,
L. Cappellacci, M. Grifantini, A. Barzi, G. Nocentini, H. Yang, A.
O'Connor, H.N. Jayaram, C. Carrell, B.M. Goldstein, Furanfurin and thiophenfurin: Two 94
novel tiazofurin analogues. Synthesis, structure, antitumour activity, and interactions with inosine monophosphate dehydrogenase, J. Med. Chem. 38(19) (1995) 3829-3837. [32]
X. Li, Y. He, C.H. Ruiz, M. Koenig, M.D. Cameron, Characterization of dasatinib and its structural analogs as CYP3A4 mechanism-based inactivators and the proposed bioactivation pathways, Drug Metab. Dispos. 37(6) (2009) 1242-1250.
[33]
S. Hu-Lieskovan, S. Mok, B. Homet Moreno, J. Tsoi, L. Robert, L. Goedert, E.M. Pinheiro, R.C. Koya, T.G. Graeber, B. Comin-Anduix, A. Ribas, Improved antitumour activity of immunotherapy with B-RAF and MEK inhibitors in B-RAF(V600E) melanoma, Sci. Transl. Med. 18,7(279) (2015) 279-41.
[34]
M.A. Rashid, K.R. Gustafson, J.H. Cardellina, M.R. Boyd, F. Patellamide, A new cytotoxic cyclic peptide from the colonial ascidian Lissoclinum patella, J. Nat. Products. 58(4) (1995) 594-597.
[35]
Y. Yao, S. Chen, X. Zhou, L. Xie, A. Chen, 5‑FU and ixabepilone modify the microRNA expression profiles in MDA‑MB‑453 triple‑negative breast cancer cells, Oncol. Lett. 7 (2014) 541-547.
[36]
K.H. Altmann, Epothilone B and its analogs - A new family of anticancer agents, Mini Rev. Med. Chem. 3(2) (2003) 149-158.
[37]
E. Ramadan, H.M. Hamid, S.A. Noureddin, K.O. Badahdah, Synthesis, characterization, and antitumor activity of some novel S-functionalized benzo[d]thiazole-2-thiol derivatives; regioselective coupling to the –SH group. J. Chem. Sci. 73(9) (2018) 647-654.
[38]
Y. Lu, C.M Li, Z. Wang, J. Chen, M.L. Mohler, W. Li, J.T. Dalton, D.D. Miller, Design, synthesis, and SAR studies of 4-substituted methoxylbenzoyl-aryl-thiazoles analogues as potent and orally bioavailable anticancer agents, J. Med. Chem. 54 (2011) 4678-4693.
[39]
R. Morigi, A. Locatelli, A. Leoni, M. Rambaldi, Recent patents on thiazole derivatives endowed with antitumour activity, Recent Pat. Anti-Cancer Drug Discov. 10 (2015) 280297.
[40]
H. He, X. Wang, L. Shi, W. Yin, Z. Yang, H. He, Y. Liang, Synthesis, antitumour activity and mechanism of action of novel 1,3-thiazole derivatives containing hydrazide-hydrazone and carboxamide moiety, Bioorg. Med. Chem. Lett. 26(14) (2016) 3263-3270.
[41]
Y. Lu, C. Li, Z. Wang, C.R. Ross, J. Chen, J. Dalton, W. Li, D.D. Miller, Discovery of 4substituted methoxybenzoyl-aryl-thiazole as novel anticancer agents: Synthesis, biological evaluation and structure-activity relationships, J. Med. Chem. 52(6) (2009) 1701-1711.
95
[42]
S.P. Shaik, V.L. Nayak, F. Sultana, A.V. Rao, A.B. Shaik, K.S. Babu, A. Kamal, Design and synthesis of imidazo[2,1-b]thiazole linked triazole conjugates: microtubuledestabilizing agents, Eur. J. Med. Chem. 126 (2017) 36-51.
[43]
T.I. Santana, M.O. Barbosa, P.A. Gomes, A.C. da Cruz, T.G. da Silva, A.C. Lima Leite. Synthesis, anticancer activity and mechanism of action of new thiazole derivatives, Eur. J. Med. Chem. 144 (2018) 874-886.
[44]
P. Lv, D. Li, Q. Li, X. Lu, Z. Xiao, H. Zhu. Synthesis, molecular docking and evaluation of thiazolyl-pyrazoline derivatives as EGFR TK inhibitors and potential anticancer agents, Bioorg. Med. Chem. Lett. 21 (2011) 5374-5377.
[45]
D. Secci, S. Carradori, B. Bizzarri, A. Bolasco, P. Ballario, Z. Patramani, P. Fragapane, S. Vernarecci, C. Canzonetta, P. Filetici, Synthesis of a novel series of thiazole-based histone acetyltransferase inhibitors, Bioorg. Med. Chem. 22(2014) 1680-1689.
[46]
S. Mirza, S.A. Naqvi, K.M. Khan, U. Salar, M.I. Choudhary, Facile synthesis of novel substituted aryl-thiazole (SAT) analogs via one pot multi-component reaction as potent cytotoxic agents against cancer cell lines, Bioorg. Chem. 70 (2017) 133-143.
[47]
M.A. Ewida, D.A. El Ella, D.S. Lasheen, H.A. Ewida, Y.I. El-Gazzar, H.I. El-Subbagh, Thiazolo[4,5-d]pyridazine analogues as a new class of dihydrofolate reductase (DHFR) inhibitors: Synthesis, biological evaluation and molecular modeling study, Bioorg. Chem. 74 (2017) 228-237.
[48]
V.K. Patel, A. Singh, D.K. Jain, A.K. Sharma, A.K. Gupta, P.C. Sharma, H. Rajak, Development of structure activity correlation model on 4-quinolones derivatives as tubulin polymerization inhibitors: rational to advance the understanding of structure activity profile, Drug Discov. Devel. 1(1) (2014) 1-16.
[49]
H. Rajak, A. Singh, K. Raghuwanshi, P.K. Dewangan, R. Veerasamy, P.C. Sharma, Dixit, P.A. Mishra, Structural insight into hydroxamic acid based histone deacetylase inhibitors for the presence of anticancer activity, Curr. Med. Chem. 21 (2014) 2642-2664.
[50]
D.K. Jain, A. Singh, V.K. Patel, P.C. Sharma, A.K. Gupta, A.K. Sharma, H. Rajak. Hydroxamic acid based histone deacetylase inhibitors: Present and future prospective as anticancer agent, Int. J. Pharm. Pharm. Sci. 6 (2014) 648-650.
[51]
P.C. Sharma, A. Sinhmar, A. Sharma, H. Rajak, D.P. Pathak, Medicinal Significance of Benzothiazole Scaffold: An Insight View, J. Enzyme Inhib. Med. Chem. 28(2) (2013) 240-266.
96
[52]
P.C. Sharma, M. Chaudhary, A. Sharma, A. Piplani, H. Rajak, O. Prakash, Insight View on Possible Role of Fluoroquinolones in Cancer Therapy, Curr. Top. Med. Chem. 13(16) (2013) 2076-2096.
[53]
H. Rajak, A. Singh, P.K. Dewangan, V. Patel, D.K. Jain, S.K. Tiwari, R. Veerasamy, P.C. Sharma, Peptide based macrocycles: Selective histone deacetylase inhibitors with antiproliferative activity, Curr. Med. Chem. 20 (2013) 1887-1903.
[54]
H. Rajak, P.K. Dewangan, V. Patel, D.K. Jain, A. Singh, R. Veerasamy, P.C. Sharma, A. Dixit. Design of combretastatin A4 analoges as tubulin target vascular disrupting agents with special emphasis on their Cis-restricted isomers, Curr. Pharm. Des. 19(10) (2013) 1923-1955.
[55]
H. Rajak, P. Kumar, P. Parmar, B.S. Thakur, R. Veerasamy, P.C. Sharma, A.K. Sharma, A.K. Gupta, J.S. Dangi, Appraisal of GABA and PABA as linker: Design and synthesis of novel benzamide based histone deacetylase inhibitors, Eur. J. Med. Chem. 53 (2012) 390397.
[56]
H. Rajak, A. Agarawal, P. Parmar, B.S. Thakur, R. Veerasamy, P.C. Sharma, M.D. Kharya, 2,5-Disubstituted-1,3,4-oxadiazoles / thiadiazole as surface recognition moiety: Design and synthesis of novel hydroxamic acid based histone deacetylase inhibitors, Bioorg. Med. Chem. Lett. 21 (2011) 5735-5738.
[57]
D. Griffith, P. Parker, C.J. Marmion, Enzyme inhibition as a key target for the development of novel metal-based anti-cancer therapeutics, Anticancer Agents Med. Chem. 10(5) (2010) 354-370.
[58]
S.K. Hanks, A.M. Quinn, T. Hunter, The protein kinase family: Conserved features and deduced phylogeny of the catalytic domains. Science 241(4861) (1988) 42-52.
[59]
M.K. Paul, A.K. Mukhopadhyay, Tyrosine kinase-role and significance in cancer, Int. J. Med. Sci. 1(2) (2004)101-115.
[60]
D.R. Robinson, Y.M. Wu, S.F. Lin, The protein tyrosine kinase family of the human genome, Oncogene 19(49) (2000) 5548-57.
[61]
E. Zwick, J. Bange, A. Ullrich, Receptor tyrosine kinase signalling as a target for cancer intervention strategies, Endocrine-related cancer 8(3) (2001) 161-73.
[62]
R.M. Strieter, Masters of angiogenesis, Nat. Med. 11 (2005) 925-7.
[63]
V.V. Padma, An overview of targeted cancer therapy, Biomedicine (Taipei) 5(4) (2015) 19. 97
[64]
R. Munagala, F. Aqil, R.C. Gupta, Promising molecular targeted therapies in breast cancer, Indian J. Pharmacol. 43(3) (2011) 236-45.
[65]
S.R. Hubbard, W.T. Miller, Receptor tyrosine kinases: mechanisms of activation and signalling, Curr. Opin. Cell Biol. 19(2) (2007) 117-123.
[66]
M.A. Lemmon, J. Schlessinger, Cell signaling by receptor tyrosine kinases, Cell 141(7) (2010) 1117-1134.
[67]
P. Seshacharyulu, M.P. Ponnusamy, D. Haridas, M. Jain, A.K. Ganti, S.K. Batra, Targeting the EGFR signaling pathway in cancer therapy, Expert Opin. Ther. Tar. 16(1) (2012) 15-31.
[68]
J. Carlsson, H. Nordgren, J. Sjostrom, K. Wester, K. Villman, N.O. Bengtsson, B. Ostenstad, H. Lundqvist, C. Blomqvist, HER2 expression in breast cancer primary tumours and corresponding metastases, Original data and literature review, British J. Cancer 90(12) (2004) 2344-8.
[69]
A. Sebastian, V. Pandey, C.D. Mohan, Y.T. Chia, S. Rangappa, J. Mathai, C.P. Baburajeev, S. Paricharak, L.H. Mervin, K.C. Bulusu, J.E. Fuchs, A. Bender, S. Yamada, Basappa, P.E. Lobie, K.S. Rangappa, Novel adamantanyl-based thiadiazolyl pyrazoles targeting EGFR in triple-negative breast cancer, ACS Omega 1 (2016) 1412-1424.
[70]
H. Wang, K. Qiu, H. Cui, Y. Yang, Yin-Luo, M. Xing, X. Qiu, L. Bai, H. Zhu, Synthesis, molecular docking and evaluation of thiazolyl-pyrazoline derivatives containing benzodioxole as potential anticancer agents, Bioorg. Med. Chem. 21 (2013) 448-455.
[71]
H. Ding, Z. Chen, C. Zhang, T. Xin, Y. Wang, H. Song, Y. Jiang, Y. Chen, Y. Xu, C. Tan, Synthesis and cytotoxic activity of some novel N-pyridinyl-2-(6-phenylimidazo[2,1b]thiazol-3-yl)acetamide derivatives, Molecules 17 (2012) 4703-4716.
[72]
P.C. Lv, C.F. Zhou, J. Chen, P.G. Liu, K.R. Wang, W.J. Mao, H.O. Li, Y. Yang, J. Xiong, H.L Zhu, Design, synthesis and biological evaluation of thiazolidinone derivatives as potential EGFR and HER-2 kinase inhibitors, Bioorg. Med. Chem. 18 (2010) 314-319.
[73]
U. Bhanushali, S. Rajendran, K. Sarma, P. Kulkarni, K. Chatti, S. Chatterjee, C.S. Ramaa, 5-Benzylidene-2,4-thiazolidenedione derivatives: Design, synthesis and evaluation as inhibitors of angiogenesis targeting VEGR-2, Bioorg. Chem. 67 (2016) 139-147.
[74]
E. Gonzalez, T.E. McGraw, The Akt kinases: isoform specificity in metabolism and cancer, Cell Cycle 8(16) (2009) 2502-2508.
98
[75]
A. Bellacosa, C.C. Kumar, A. Di Cristofano, J.R. Testa, Activation of AKT kinases in cancer: implications for therapeutic targeting, Adv. Cancer Res. 94 (2005) 29-86.
[76]
S. Chang, Z. Zhang, X. Zhuang , J. Luo, X. Cao, H. Li, Z. Tu, X. Lu, X. Ren, K. Ding, New thiazole carboxamides as potent inhibitors of Akt kinases, Bioorg. Med. Chem. Lett. 22 (2012) 1208-1212.
[77]
M.D. Altıntop, B. Sever, C. G. Akalın, A. Ozdemir, Design, synthesis, and evaluation of a new series of thiazole-based anticancer agents as potent Akt Inhibitors, Molecules 23 (2018) 1318.
[78]
L.E. Ling, W.C. Lee. Tgf-beta type I receptor (Alk5) kinase inhibitors in oncology, Curr. Pharm. Biotechnol. 12(12) (2011) 2190-202.
[79]
D. Kim, J.H. Choi, Y.J. Ana, H.S. Lee, Synthesis and biological evaluation of 5-(pyridin2-yl) thiazoles as transforming growth factor-b type1 receptor kinase inhibitors, Bioorg. Med. Chem. Lett. 18 (2008) 2122-2127.
[80]
H. Amada, Y. Sekiguchi, N. Ono, T. Koami, T. Takayama, T. Yabuuchi, H. Katakai, A. Ikeda, M. Aoki, T. Naruse, R. Wada, A. Nozoe, M. Sato, 5-(1,3-Benzothiazol-6-yl)-4-(4methyl-1,3-thiazol-2-yl)-1H-imidazole derivatives as potent and selective transforming growth factor-β type I receptor inhibitors, Bioorg. Med. Chem. 20(24) (2012) 7128-38.
[81]
H. Amada, Y. Sekiguchi, N. Ono, Y. Matsunaga, T. Koami, H. Asanuma, F. Shiozawa, M. Endo, A. Ikeda, M. Aoki, N. Fujimoto, R. Wada, M. Sato, Design, synthesis, and evaluation of novel 4-thiazolylimidazoles as inhibitors of transforming growth factor-β type I receptor kinase. Bioorg. Med. Chem. Lett. 22(5) (2012) 2024-2029.
[82]
S. Gaillard, V. Stearns, Aromatase inhibitor-associated bone and musculoskeletal effects: new evidence defining etiology and strategies for management, Breast Cancer Res. 13(2) (2011) 1-11.
[83]
M.J. Balunas, B. Su, R.W. Brueggemeier, A.D. Kinghornb, Natural products as aromatase inhibitors, Anticancer Agents Med. Chem. 8(6) (2008) 646-682.
[84]
S. Abdelrahman, A.S. Mayhoub, L. Marler, P. Tamara, T.P. Kondratyuk, Park Eun-Jung, M. John, J.M. Pezzuto, M. Cushman,Optimization of the aromatase inhibitory activities of pyridylthiazole analogues of resveratrol, Bioorg. Med. Chem. 20 (2012) 2427-2434.
[85]
T.T. Tunga, D.T. Oanha, P.T. Dunga, V.T. Huea, H.H. Parkb, B.W. Hanb, Y. Kimc, J.T. Hongc, S.B. Han, N.H. Nam, New Benzothiazole/thiazole-containing hydroxamic acids as potent histone deacetylase inhibitors and antitumour agents, Med. Chem. 9 (2013) 10511057.
99
[86]
S. Anandan, J.S. Ward, R.D. Brokx, T. Denny, M.R. Bray, D.V. Patel, X. Xiao, Design and synthesis of thiazole-5-hydroxamic acids as novel histone deacetylase inhibitors, Bioorg. Med. Chem. Lett. 17 (2007) 5995-5999.
[87]
S. Carradori, D. Rotili, C. De Monte, A. Lenoci, M. D’Ascenzio, V. Rodriguez, P. Filetici, M. Miceli, A. Nebbioso, L. Altucci, D. Secci, A. Mai, Evaluation of a large library of (thiazol-2-yl) hydrazones and analogues as histone acetyltransferase inhibitors: Enzyme and cellular studies, Eur. J. Med. Chem. 80 (2014) 569-578.
[88]
D.T.K. Oanh, H.V. Hai, S.H. Park, H. Kim, B. Han, H. Kim, J. Hong, S. Han,V.T.M. Hue, N. Nam, Benzothiazole-containing hydroxamic acids as histone deacetylase inhibitors and antitumour agents, Bioorg. Med. Chem. Lett. 21 (2011) 7509-7512.
[89]
M.Y. Zhao, Y. Yin, X. Yu, C.B. Sangani, S. Wanga, A. Lu, L. Yang, P. Lv, M. Jiang, H. Zhu, Synthesis, biological evaluation and 3D-QSAR study of novel 4,5-dihydro-1Hpyrazole thiazole derivatives as B-RAF(V600E) inhibitors, Bioorg. Med. Chem. 23 (2015) 46-54.
[90]
M.S. Abdel-Maksoud, M.R. Kim, M.I. El-Gamal, M.M. Gamal El-Din, J. Tae, H.S. Choi, K. Lee, K.H. Yoo, C. Oh, Design, synthesis, in vitro antiproliferative evaluation, and kinase inhibitory effects of a new series of imidazo[2,1-b]thiazole derivatives, Eur. J. Med. Chem. 95 (2015) 453-463.
[91]
F. Musumeci, S. Schenone, C. Brullo, M. Botta, An update on dual Src/Abl inhibitors, Future Med. Chem. 4(6) (2012) 799-822.
[92]
J. Cai, M. Sun, X. Wu, J. Chen, P. Wang, X. Zong, M. Ji, Design and synthesis of novel 4benzothiazole amino quinazolines dasatinib derivatives as potential anti-tumour agents, Eur. J. Med. Chem. 63 (2013) 702-712.
[93]
L.J. Lombardo, F.Y. Lee, P. Chen, D. Norris, J.C. Barrish, K. Behnia, S. Castaneda, L.A.M. Cornelius, J. Das, A.M. Doweyko, C. Fairchild, J.T. Hunt, I. Inigo, K. Johnston, A. Kamath, D. Kan, H. Klei, P. Marathe, S. Pang, R. Peterson, S. Pitt, G.L. Schieven, R.J. Schmidt, J. Tokarski, M. Wen, J. Wityak, R.M. Borzilleri, Discovery of N-(2-Chloro-6methyl-phenyl)-2-(6-(4-(2-hydroxyethyl)-piperazin-1-yl)-2-methylpyrimidin-4- ylamino) thiazole-5-carboxamide (BMS-354825), A dual Src/Abl kinase inhibitor with potent antitumour activity in preclinical assays, J. Med. Chem. 47 (2004) 6658-6661.
[94]
E. Mukhtar, V.M. Adhami, H. Mukhtar, Targeting microtubules by natural agents for cancer therapy, Mol. Cancer Ther. 13(2) (2014) 275-284.
[95]
C. Dumontet, M.A. Jordan, Microtubule-binding agents: a dynamic field of cancer therapeutics, Nat. Rev. Drug Discov. 9(10) (2010) 790-803. 100
[96]
A.L. Parker, M. Kavallaris, J.A. McCarroll, Microtubules and their role in cellular stress in cancer, Front Oncol. 4 (2014) 153.
[97]
A. Kryshchyshyn, D. Atamanyuk, R. Lesyk, Fused thiopyrano [2, 3-d] thiazole derivatives as potential anticancer agents, Sci. Pharm. 80 (2012) 509-529.
[98]
K. Ohsumi, T. Hatanaka, K. Fujita, R. Nakagawa, Y. Fukuda, Y. Nihei, Y. Suga, Y. Morinaga, Y. Akiyama, T. Tsuji, Syntheses and antitumour activity of cis-restricted combretastatins: 5-Membered heterocyclic analogues, Bioorg. Med. Chem. Lett. 8 (1998) 3153-3158.
[99]
R. Romagnoli, P.G. Baraldi, M.K. Salvador, M.E. Camacho, D. Preti, M.A. Tabrizi, M. Bassetto, A. Brancale, E. Hamel, R. Bortolozzi, G. Basso, G. Viola, Synthesis and biological evaluation of 2-substituted-4-(3’,4’,5’-trimethoxy phenyl)-5-aryl thiazoles as anticancer agents, Bioorg. Med. Chem. 20 (2012) 7083-7094.
[100] Z. Liu, Y. Wang, Z. Li, J. Jiang, D. Boykin, Synthesis and anticancer activity of novel 3, 4-diarylthiazol-2(3H)-ones (imines), Bioorg. Med. Chem. Lett. 19 (2009) 5661-5664. [101] A.V. Rao, K. Swapna, S.P. Shaik, V.L. Nayak, T.S. Reddy, S. Sunkari, T.B. Shaik, C. Bagul, A. Kamal, Synthesis and biological evaluation of cis-restricted triazole/tetrazole mimics of combretastatin-benzothiazole hybrids as tubulin polymerization inhibitors and apoptosis inducers, Bioorg. Med. Chem. 25 (2017) 977-999. [102] M. Sun, Q. Xu, J. Xu, Y. Wu, Y. Wang, D. Zuo, Q. Guan, K. Bao, J. Wang, Y. Wu, W. Zhang, Synthesis and bio-evaluation of N,4-diaryl-1,3-thiazole-2-amines as tubulin inhibitors with potent antiproliferative activity, Plos One 12(3) (2017) 1-15. [103] T.B. Shaik, S.M.A Hussaini, V.L. Nayak, M.L. Sucharitha, M.S. Malik, A. Kamal. Rational design and synthesis of 2-anilinopyridinyl-benzothiazole schiff bases as antimitotic agents, Bioorg. Med. Chem. Lett. 27 (2017) 2549-2558. [104] M. Banimustafa, A. Kheirollahi, M. Safavi, S.K. Ardestani, H. Aryapour, A. Foroumadi, S. Emami, Synthesis and biological evaluation of 3-(trimethoxyphenyl)-2(3H)-thiazole thiones as combretastatin analogs, Eur. J. Med. Chem. 70 (2013) 692-702. [105] S.P. Shaik, M. Vishnuvardhan, F. Sultana, A.V.S. Rao, C. Bagul, D. Bhattacharjee, J.S. Kapure, N. Jain, A. Kamal, Design and synthesis of 1,2,3-triazolo linked benzo[d]imidazo[2,1-b]thiazole conjugates as tubulin polymerization inhibitors, Bioorg. Med. Chem. 2017. [Article in Press]. [106] M. Salehi, M. Amini, S.N. Ostad , G.H. Riazi, A. Assadieskandar, B. Shafiei, A. Shafiee, Synthesis, cytotoxic evaluation and molecular docking study of 2-alkylthio-4-(2,3,4-
101
trimethoxyphenyl)-5-aryl-thiazoles as tubulin polymerization inhibitors, Bioorg. Med. Chem. 21 (2013) 7648-7654. [107] S.D. Guggilapu, L. Guntuku, T.S. Reddy, A. Nagarsenkar, D.K. Sigalapalli, V.G.M. Naidu, S.K. Bhargava, N.B. Bathini, Synthesis of thiazole linked indolyl-3-glyoxylamide derivatives as tubulin polymerization inhibitors, Eur. J. Med. Chem. 138 (2017) 83-95. [108] M.F. Baig, V.L. Nayak, P. Budaganaboyina, K. Mullagiri, S. Sunkari, J. Gour, A. Kamal. Synthesis and biological evaluation of imidazo [2, 1-b] thiazole benzimidazole conjugates as microtubule-targeting agents, Bioorg. Chem. 77 (2018) 515-526. [109] F. Wang, Z. Yang, Y. Liu, L. Ma, Y. Wu, L. He, M. Shao, K. Yu, W. Wu, Y. Pu, C. Nie, L. Chen, Synthesis and biological evaluation of diarylthiazole derivatives as antimitotic and antivascular agents with potent antitumour activity, Bioorg. Med. Chem. 23 (2015) 3337-3350. [110] J.C. Wang, Cellular roles of DNA topoisomerases: a molecular perspective, Nat. Rev. Mol. Cell Biol. 3 (2002) 430-440. [111] J.L. Nitiss, DNA topoisomerase II and its growing repertoire of biological functions. Nat. Rev. Cancer 9(5) (2009) 327–337. [112] S. Choi, H.J. Park, S.K. Lee, S.W. Kim, G. Han, H.P. Choo, Solid phase combinatorial synthesis of benzothiazoles and evaluation of topoisomerase II inhibitory activity, Bioorg. Med. Chem. 14 (2016) 1229-1235. [113] Y. Cheng, S.R. Avula, W. Gao, D. Addla, V.K.R. Tangadanchu, L. Zhang, J. Lin, C. Zhou,
Multi-targeting exploration of new 2-aminothiazolyl quinolones: Synthesis,
antimicrobial evaluation, interaction with DNA, combination with topoisomerase IV and penetrability into cells, Eur. J. Med. Chem. 124 (2016) 935-945. [114] A. Beauchard, A. Jaunet, L. Murillo, B. Baldeyrou, A. Lansiaux, J. Cherouvrier, L. Domon, L. Picot, C. Bailly, T. Besson, V. Thiery, Synthesis and antitumoural activity of novel
thiazolobenzotriazole,
thiazoloindolo[3,2-c]quinoline
and
quinolinoquinoline
derivatives, Eur. J. Med. Chem. 44 (2009) 3858-3865. [115] A. Reichelt , J.M. Bailis, M.D. Bartberger, G. Yao, H. Shu, M.R. Kaller, J.G. Allen, M.F. Weidner, K.S. Keegan, J.H. Dao, Synthesis and structure activity relationship of trisubstituted thiazoles as Cdc7 kinase inhibitors, Eur. J. Med. Chem. 80 (2014) 364-382. [116] O. Afzal, M.S. Akhtar, S. Kumar, M.R. Ali, M. Jaggi, S. Bawa, Hit to lead optimization of a series of N-[4-(1,3-benzothiazol-2-yl)phenyl]acetamides as monoacylglycerol lipase inhibitors with potential anticancer activity, Eur. J. Med. Chem. 121 (2016) 318-330.
102
[117] F. Lefranc, Z. Xu, P. Burth, V. Mathieu, G. Revelant, M.V. de Castro Faria, C. Noyon, D.G. Garcia, D. Dufour, C. Bruyere, C.F. Gonçalves-de-Albuquerque, P.V. Antwerpen, B. Rogister, S. Hesse, G. Kirsch, R. Kiss, 4-Bromo-2-(piperidin-1-yl)thiazol-5-yl-phenyl methanone (12b) inhibits Na+/K+-ATPase and Ras oncogene activity in cancer cells, Eur. J. Med. Chem. 63 (2013) 213-223. [118] D.A. Ibrahim, D.S. Lasheen, M.Y. Zaky, A.W. Ibrahim, D. Vullo, M. Ceruso, C.T. Supuran, D.A. El Ella, Design and synthesis of benzothiazole-6-sulfonamides acting as highly potent inhibitors of carbonic anhydrase isoforms I, II, IX and XII, Bioorg. Med. Chem. 23 (2015) 4989-4999. [119] S.K. Suthar, S. Bansal, S. Lohan, V. Modak, A. Chaudhary, A. Tiwari, Design and synthesis of novel 4-(4-oxo-2-arylthiazolidin-3-yl) benzenesulfonamides as selective inhibitors of carbonic anhydrase IX over I and II with potential anticancer activity, Eur. J. Med. Chem. 66 (2013) 372-379. [120] D. Vogt, J. Weber, K. Ihlefeld, A. Bruggerhoff, E. Proschak, H. Stark, Design, synthesis and evaluation of 2-aminothiazole derivatives as sphingosine kinase inhibitors, Bioorg. Med. Chem. 22 (2014) 5354-5367. [121] P. Franchetti, L. Cappellacci, M. Pasqualini, R. Petrelli, V. Jayaprakasan, H.N. Jayaram, D.B. Boyd, M.D. Jaind, M. Grifantinia. Synthesis, conformational analysis, and biological activity of new analogues of thiazole-4-carboxamide adenine dinucleotide (TAD) as IMP dehydrogenase inhibitors, Bioorg. Med. Chem. 13 (2005) 2045-2053. [122] H. Zhao, G. Cui, J. Jin, X. Chen, B. Xu, Synthesis and Pin1 inhibitory activity of thiazole derivatives, Bioorg. Med. Chem. 24 (2016) 5911-5920. [123] C. Chen, J. Song, J. Wanga, C. Xu, C. Chen, W. Gu, H. Sun, X. Wena, Synthesis and biological evaluation of thiazole derivatives as novel USP7 Inhibitors, Bioorg. Med. Chem. Lett. 27 (2017) 845-849. [124] L. Yan, N. Rosen, C. Arteaga, Targeted therapies: A new generation of cancer treatments, Chin. J. Cancer 30(1) (2011) 1-4. [125] D. Kaminskyy, G.J.M. den Hartog, M. Wojtyra, M. Lelyukh, A. Gzella, A. Bast, R. Lesyk, Antifibrotic and anticancer action of 5-ene amino/Iminothiazolidinones, Eur. J. Med. Chem. 112 (2016) 180-195. [126] R.S. Giri, H.M. Thaker, T. Giordano, B. Chen, S. Nuthalapaty, K.K. Vasu, V. Sudarsanam, Synthesis and evaluation of quinazolinone derivatives as inhibitors of NFkB, AP-1 mediated transcription and eIF-4E mediated translational activation: Inhibitors of multi-pathways involve in cancer, Eur. J. Med. Chem. 45 (2010) 3558-3563. 103
[127] L. Xie, J. Huanga, X. Chena, H. Yu, K. Lia, D. Yang, X. Chen, J. Ying, F. Pan, Y. Lv, Y. Cheng, Design, synthesis and biological evaluation of novel rapamycin benzothiazole hybrids as mTOR targeted anti-cancer agents, Chem. Pharm. Bull. 64(4) (2016) 346-55. [128] A.R. Ali, E.R. El-Bendary, M.A. Ghaly, I.A. Shehata, Synthesis, in vitro anticancer evaluation and in silico studies of novel imidazo[2,1-b]thiazole derivatives bearing pyrazole moieties, Eur. J. Med. Chem. 75 (2014) 492-500. [129] X. Xie, H. Li, J. Wang, S. Mao, M. Xin, S. Lu, Q. Mei, S. Zhang, Synthesis and anticancer effects
evaluation
of
1-alkyl-3-(6-(2-methoxy-3-sulfonylaminopyridin-5-
yl)benzo[d]thiazol-2-yl)urea as anticancer agents with low toxicity, Bioorg. Med. Chem. 23 (2015) 6477-6485. [130] H. Li, X. Wang, J. Wang, T. Shao, Y. Li, Q. Mei, S. Lu, S. Zhang, Combination of 2methoxy-3-phenylsulfonylaminobenzamide and 2-aminobenzothiazole to discover novel anticancer agents, Bioorg. Med. Chem. 22 (2014) 3739-3748. [131] M. Hayakawa, H. Kaizawa, K. Kawaguchi, N. Ishikawa, T. Koizumi, T. Ohishi, M. Yamano, M. Okada, M. Ohta, S. Tsukamoto, F. Raynaud, M.D. Waterfield, P. Parkerd, P. Workman, Synthesis and biological evaluation of imidazo[1,2-a]pyridine derivatives as novel PI3 kinase p110a inhibitors, Bioorg. Med. Chem. 15 (2007) 403-412. [132] R.A. Fairhurst, M. Gerspacher, P. Imbach-Weese, R. Mah, G. Caravatti, P. Furet, C. Fritsch, C. Schnell, J. Blanz, F. Blasco, S. Desrayaud, D.A. Guthy, M. Knapp, D. Arz, J. Wirth, E. Roehn-Carnemolla, V.H Luu, Identification and optimisation of 4,5dihydrobenzo [1,2-d:3,4-d]bisthiazole and 4,5-dihydrothiazolo[4,5-h]quinazoline series of selective phosphatidylinositol-3 kinase alpha inhibitors, Bioorg. Med. Chem. Lett. 25 (2015) 3575-3581. [133] S. Xuejiao, X. Yong, W. Ningyu, Z. Lidan, S. Xuanhong, X. Youzhi, Y. Tinghong, S. Yaojie, Z. Yongxia, Y. Luoting, A novel benzothiazole derivative YLT322 induces apoptosis via the mitochondrial apoptosis pathway in vitro with anti-tumour activity in solid malignancies, Plus One 8(5) (2013) 1-10. [134] M. Choi, K.H. Jung, D. Kim, H. Lee, H. Zheng, B.H. Park, S. Hong, M. Kim, S. Hong, S. Hong, Anticancer effects of a novel compound HS-113 on cell growth, apoptosis, and angiogenesis in human hepatocellular carcinoma cells, Cancer Lett. 306 (2011) 190-196. [135] M.P. Tantaka, D.D. Mukherjee, A. Kumar, G. Chakrabarti, D. Kumar, A facile and microwave-assisted rapid synthesis of 2-arylamino-4-(3′-indolyl)-thiazoles as apoptosis inducing cytotoxic agents, Anti-Cancer Agents Med. Chem. 17 (2017) 442-455.
104
[136] G. Lotfy, M.M. Said, E.S. Ashry, E.S. El Tamany, A. Al-Dhfyan, Y.M. Abdel Aziz, A. Barakat, Synthesis of new spirooxindole-pyrrolothiazole derivatives: Anti-cancer activity and molecular docking, Bioorg. Med. Chem. 25 (2017) 1514-1523. [137] P. Kumar, M. Duhan, K. Kadyan, J.K. Bhardwaj, P. Saraf, M. Mittal, Multicomponent synthesis of some molecular hybrid containing thiazole pyrazole as apoptosis inducer, Drug Res. (Stuttg) 68(2) (2018) 72-79. [138] S.M.M. Yahya, A.O. Abdelhamid, M.M. Abd-Elhalima, G.H. Elsayeda, E.F. Eskandera, The effect of newly synthesized progesterone derivatives on apoptotic and angiogenic pathway in MCF-7 breast cancer cells. Steroids 126 (2017) 15-23. [139] W. Zhou, W. Tang, Z. Sun, Y. Li, Y. Dong, H. Pei, Y. Peng, J. Wang, T. Shao, Z. Jiang, Z. Zhen Yi, Y. Chen, Discovery and optimization of N-substituted 2-(4-pyridinyl) thiazole carboxamides against tumour growth through regulating angiogenesis signaling pathways, Sci. Rep. 6 (2016) 33-34. [140] A. Andreani, M. Granaiola, A. Leoni, A. Locatelli, R. Morigi, M. Rambaldi, L. Varoli, D. Lannigan, J. Smith, D. Scudiero, S. Kondapaka, R.H. Shoemaker, Imidazo[2,1-b]thiazole guanylhydrazones as RSK2 inhibitors, Eur. J. Med. Chem. 46 (2011) 4311-4323. [141] N.J. Wheate, C.R. Brodie, J.G. Collins, S. Kemp, J.R. Aldrich-Wright, DNA intercalators in cancer therapy: organic and inorganic drugs and their spectroscopic tools of analysis, Mini Rev. Med. Chem. 7(6) (2007) 627-48. [142] A. Grozav, L.I. Gaina, V. Pileczki, O. Crisan, L. Silaghi-Dumitrescu, B. Therrien, V. Zaharia, I. Berindan-Neagoe, The synthesis and antiproliferative activities of new arylidene-hydrazinyl-thiazole derivatives, Int. J. Mol. Sci. 15 (2014) 22059-22072. [143] F.J. Reyes-Rangel , A.K. Lopez-Rodriguez, L.V. Pastrana-Cancino, M.A. Loza-Mejia, J.D. Solano, R. Rodriguez-Sotres, A. Lira-Rocha, Synthesis, cytotoxic activity, DNA binding and molecular docking studies of novel 9-anilinothiazolo[5,4-b]quinoline derivatives, Med. Chem. Res. 25 (2016) 2976-2988. [144] V.M. Manikandamathavan, M. Thangaraj, T. Weyhermuller, R.P. Parameswari, V. Punitha, N.N. Murthy, B.U. Nair, Novel mononuclear Cu (II) terpyridine complexes, Impact of fused ring thiophene and thiazole head groups towards DNA/BSA interaction, cleavage and antiproliferative activity on HEPG2 and triple negative CAL-51 cell line, Eur. J. Med. Chem. 135 (2017) 434-446. [145] N. Fan, Q. He, M. Duan, Y. Bai, J. Tang, Synthesis and antiproliferative activity of D-ring substituted steroidal benzamidothiazoles, Steroids 112 (2016) 103-108.
105
[146] K. Kotthireddy, S. Devulapally, A. Pasula, An efficient one-pot three-component synthesis of 2-(4-(2-oxo-2H-chromen-3-yl)thiazol-2-yl)-3-arylacrylonitriles and their cytotoxic activity evaluation with molecular docking, J. Saudi Chem. Soc. 23 (2019) 325-337. [147] A. Mohammadi-Farani, A. Foroumadi, M.R. Kashani, A. Aliabadi, N-Phenyl-2-ptolylthiazole-4-carboxamide derivatives: Synthesis and cytotoxicity evaluation as anticancer agents, Iran. J. Basic Med. Sci. 17 (2014) 502-508. [148] A. Zablotskaya, I. Segal, A. Geronikaki, T. Eremkina, S. Belyakov, M. Petrova, I. Shestakova, L. Zvejniece, V. Nikolajeva, Synthesis, physicochemical characterization, cytotoxicity, antimicrobial, anti-inflammatory and psychotropic activity of new N-[1,3(benzo)thiazol-2-yl]-ω-[3,4-dihydroisoquinolin-2(1H)-yl] alkanamides, Eur. J. Med. Chem. 70 (2013) 846-856. [149] A. Cohen, M.D. Crozet, P. Rathelot, N. Azas, P. Vanelle, Synthesis and promising in vitro antiproliferative activity of sulfones of a 5-nitrothiazole series, Molecules 18 (2013) 97113. [150] A. Carbone, B. Parrino, G. Di Vita, A. Attanzio, V. Spano, A. Montalbano, P. Barraja, L. Tesorierev, P. Livrea MA Diana, G. Cirrincione, Synthesis and antiproliferative activity of thiazolyl-bis-pyrrolo[2,3-b]pyridines
and
indolyl-thiazolyl-pyrrolo[2,3-c]pyridines,
Nortopsentin analogues, Mar. Drugs 13 (2015) 460-492. [151] W. Cai, A. Liu, Z. Li, W. Dong, X. Liu, N. Sun, Synthesis and anticancer activity of novel thiazole-5-carboxamide derivatives, Appl. Sci. 6(8) (2016) 1-10. [152] A. Fallah-Tafti, A. Foroumadi, R. Tiwari, A.N. Shirazi, D. Hangauer, Y. Bu, T. Akbarzadeh, K. Parang, A. Shafiee, Thiazolyl N-benzyl-substituted acetamide derivatives: Synthesis, Src kinase inhibitory and anticancer activities, Eur. J. Med. Chem. 46 (2011) 4853-4858. [153] A.T. Taher,
H.H. Georgey, H.I. El-Subbagh, Novel 1,3,4-heterodiazole analogues:
Synthesis and in-vitro antitumour activity, Eur. J. Med. Chem. 47 (2012) 445-451. [154] C. Yeh, C. Su, J. Hwang, M. Chou, Therapeutic effects of cantharidin analogues without bridging ether oxygen on human hepatocellular carcinoma cells, Eur. J. Med. Chem. 45 (2010) 3981-3985. [155] E. Gursoy, N.U. Guzeldemirci, Synthesis and primary cytotoxicity evaluation of new imidazo [2, 1-b] thiazole derivatives, Eur. J. Med. Chem. 42 (2007) 320-326. [156] D.S. Prasanna, C.V. Kavitha, K. Vinaya, S.R. Ranganatha, S. Raghavan, K.S. Rangappa, Synthesis and Identification of a new class of antileukemic agents containing 2-
106
(arylcarboxamide)-(S)-6-amino-4,5,6,7-tetrahydrobenzo[d]thiazole, Eur. J. Med. Chem. 45 (2010) 5331-5336. [157] D. Havrylyuk, B. Zimenkovsky, O. Vasylenko, L. Zaprutko, A. Gzella, R. Lesyk, Synthesis of novel thiazolone-based compounds containing pyrazoline moiety and evaluation of their anticancer activity, Eur. J. Med. Chem. 44 (2009) 1396-1404. [158] E.L. Luzina, A.V. Popov, Synthesis and anticancer activity of N-bis (trifluoromethyl) alkyl-N’-thiazolyl and N-bis (trifluoromethyl) alkyl-N’-benzothiazolyl ureas, Eur. J. Med. Chem. 44 (2009) 4944-4953. [159] F.A. Al-Omary, G.S. Hassan, S.M. El-Messery, H.I. El-Subbagh, Substituted thiazoles V. Synthesis and antitumour activity of novel thiazolo[2,3-b]quinazoline and pyrido[4,3d]thiazolo[3,2-a]pyrimidine analogues, Eur. J. Med. Chem. 47 (2012) 65-72. [160] B. Chen, R. Zhao, B. Wang, R. Droghini, J. Lajeunesse, P. Sirard, M. Endo, B. Balasubramanian, J.C. Barrisha, A new and efficient preparation of 2-aminothiazole-5carbamides, Applications to the synthesis of the anti-cancer drug dasatinib. ARKIVOC. (vi) (2010) 32-38. [161] F.L. Gouveia, R.M.B. De Oliveira, T.B. De Oliveira, I.M. Da Silva, S.C. Do Nascimento, K.X.F.R. De Sena, J.F.C. De Albuquerque, Synthesis, antimicrobial and cytotoxic activities of some 5-arylidene-4-thioxo-thiazolidine-2-ones, Eur. J. Med. Chem. 44 (2009) 2038-2043. [162] G.A. Elmegeed, W.K.B. Khalil, R.M. Mohareb, H.H. Ahmed, M.M. Abd-Elhalim, G.H. Elsayed, Cytotoxicity and gene expression profiles of novel synthesized steroid derivatives as chemotherapeutic anti-breast cancer agents, Bioorg. Med. Chem. 19 (2011) 6860-6872. [163] G.S. Hassan, S.M. El-Messery, F.A. Al-Omary, S.T. Al-Rashood, M.I. Shabayek, Y.S. Abulfadl, E.E. Habib, S.M. El-Hallouty, W. Fayad, K.M. Mohamed, B.S. El-Menshawi, H.I. El-Subbagh, Nonclassical antifolates, part 4. 5-(2-Aminothiazol-4-yl)-4-phenyl-4H1,2,4-triazole-3-thiols as a new class of DHFR inhibitors, Synthesis, biological evaluation and molecular modelling study, Eur. J. Med. Chem. 66 (2013) 135-145. [164] G.S. Hassan, S.M. El-Messery, F.A. Al-Omary, H.I. El-Subbagh, Substituted thiazoles VII. Synthesis and antitumour activity of certain 2-(substituted amino)-4-phenyl-1,3thiazole analogs, Bioorg. Med. Chem. Lett. 22 (2012) 6318-6323. [165] H.M. Refaat, Synthesis and anticancer activity of some novel 2-substituted benzimidazole derivatives, Eur. J. Med. Chem. 45 (2010) 2949-2956.
107
[166] I. Hutchinson, M. Chua, H.L. Browne, V. Trapani, T.D. Bradshaw, A.D. Westwell, M.F.G. Stevens, Antitumour benzothiazoles, Synthesis and in vitro biological properties of fluorinated 2-(4-aminophenyl)benzothiazoles, J. Med. Chem. 44 (2001) 1446-1455. [167] A. Grozav, L.I. Gaina, V. Pileczki, O. Crisan, L. Silaghi-Dumitrescu, B. Therrien, V. Zaharia, I. Berindan-Neagoe, The synthesis and antiproliferative activities of new arylidene-hydrazinyl-thiazole derivatives, Int. J. Mol. Sci. 15 (2014) 22059-22072. [168] K.M. Dawood, T.M.A. Eldebss, H.S.A El-Zahabi, M.H. Yousef, P. Metz, Synthesis of some new pyrazole-based 1,3-thiazoles and 1,3,4-thiadiazoles as anticancer agents, Eur. J. Med. Chem. 70 (2013) 740-749. [169] L. Mosula, B. Zimenkovsky, D. Havrylyuk, A. Missir, I.C. Chirita, R. Lesyk, Synthesis and antitumour activity of novel 2-thioxo-4-thiazolidinones with benzothiazole moieties, Farmacia 57(3) (2009) 321-330. [170] N.C. Desai, N. Bhatt, H. Somani, A. Trivedi, Synthesis, antimicrobial and cytotoxic activities of some novel thiazole clubbed 1,3,4-oxadiazoles, Eur. J. Med. Chem. 67 (2013) 54-59. [171] N. Zhua, Y. Ling, X. Lei, V. Handratta, A.M.H. Brodie, Novel P45017α inhibitors: 17-(2’oxazolyl)- and 17-(2’-thiazolyl)-androstene derivatives, Steroids 68 (2003) 603-611. [172] R.M. Mohareb, W.W. Wardakhan, G.A. Elmegeed, R.M.S. Ashour, Heterocyclizations of pregnenolone, Novel synthesis of thiosemicarbazone, thiophene, thiazole, thieno[2,3b]pyridine derivatives and their cytotoxicity evaluations, Steroids 77 (2012) 1560-1569. [173] R.M. Mohareb, F. Al-Omran, Reaction of pregnenolone with cyanoacetylhydrazine: Novel synthesis of hydrazide–hydrazone, pyrazole, pyridine, thiazole, thiophene derivatives and their cytotoxicity evaluations, Steroids 77 (2012) 1551-1559. [174] R.M. Mohareb, N.N.E. El-Sayed, M.A. Abdelaziz, Uses of cyanoacetylhydrazine in heterocyclic synthesis: Novel synthesis of pyrazole derivatives with anti-tumour activities, Molecules 17 (2012) 8449-8463. [175] R.M. Mohareb, D.H. Fleita, O.K. Sakka, Novel synthesis of hydrazide-hydrazone derivatives and their utilization in the synthesis of coumarin, pyridine, thiazole and thiophene derivatives with antitumour activity, Molecules 16 (2011) 16-27. [176] R.R.Reis, E.C. Azevedo, M.C.B.V. de Souza, V.F. Ferreira, R.C. Montenegro, A.J. Araujo, C. Pessoa, L.V. Costa-Lotufo, M.O. de Moraes, D.B.M. Jose Filho, A.M.T. de Souza, N.C.de Carvalho, H.C. Castro, C.R. Rodrigues, T.R.A. Vasconcelos, Synthesis and anticancer
activities
of
some
novel
2-(benzo[d]thiazol-2-yl)-8-substituted-2H-
pyrazolo[4,3-c]quinolin-3(5H)-ones, Eur. J. Med. Chem. 46 (2011) 1448-1452. 108
[177] R. Chaniyara, S.K. Tala, C. Chen, P. Lee, R. Kakadiya, H. Dong, B. Marvania, C. Chen, T. Chou, T. Lee, A. Shah, T. Su, Synthesis and antitumour evaluation of novel benzo[d]pyrrolo[2,1-b]thiazole derivatives, Eur. J. Med. Chem. 53 (2012) 28-40. [178] R. Romagnoli, P.G. Baraldi, C.L. Cara, M.K. Salvador, R. Bortolozzi, G. Basso, G. Viola, J. Balzarini, A. Brancale, X. Fu, J. Li, S. Zhang, E. Hamel, One-pot synthesis and biological evaluation of 2-pyrrolidinyl-4-amino-5-(3’,4’,5’ trimethoxy benzoyl)thiazole: A unique, highly active antimicrotubule agent, Eur. J. Med. Chem. 46 (2011) 6015-6024. [179] S.M. Rida, F.A. Ashour, S.A.M. El-Hawash, M.M. ElSemary, M.H. Badr, M.A. Shalaby, Synthesis of some novel benzoxazole derivatives as anticancer, anti-HIV-1 and antimicrobial agents, Eur. J. Med. Chem. 40 (2005) 949-959. [180] S. Bondock, S. Adel, H.A. Etman, F.A. Badria, Synthesis and antitumour evaluation of some new 1,3,4-oxadiazole-based heterocycles, Eur. J. Med. Chem. 48 (2012) 192-199. [181] S.I. Kovalenko, I.S. Nosulenko, A.Y. Voskoboynik, G.G. Berest, L.N. Antypenko, A.N. Antypenko, A.M. Katsev, Substituted 2-[(2-oxo-2H-[1,2,4]triazino[2,3-c]quinazolin-6yl)thio]acetamides with thiazole and thiadiazole fragments, Synthesis, physicochemical properties, cytotoxicity, and anticancer activity, Sci. Pharm. 80 (2012) 837-865. [182] S.A.F. Rostom, Synthesis and in vitro antitumour evaluation of some indeno [1,2-c]pyrazol(in)es substituted with sulfonamide, sulfonylurea(-thiourea) pharmacophores, and some derived thiazole ring systems, Bioorg. Med. Chem. 14 (2006) 6475-6485. [183] K.Z. Laczkowski, M. Switalska, A. Baranowska-Laczkowska, T. Plech, A. Paneth, K. Misiura, J. Wietrzyk, B. Czaplinska, A. Mrozek-Wilczkiewicz, K. Malarz, R. Musiol, I. Grela, Thiazole-based nitrogen mustards: Design, synthesis, spectroscopic studies, DFT calculation, molecular docking, and antiproliferative activity against selected human cancer cell lines, J. Mol. Structure 1119 (2016) 139-150. [184] S.A.F. Rostom, H.M. Faidallah, M.F. Radwan, M.H. Badr, Bifunctional ethyl 2-amino-4methylthiazole-5-carboxylate derivatives: Synthesis and in vitro biological evaluation as antimicrobial and anticancer agents, Eur. J. Med. Chem. 76 (2014) 170-181. [185] S.H.L.Kok, C.H. Chui, W. S. Lam, J. Chen, F.Y. Lau, R.S.M. Wong, G.Y.M. Cheng, P.Bo SanLai, T.W.T. Leung, M.W.Y. Yu, J.C. Tanga, A.S.ChiChan, Synthesis and structure evaluation of a novel cantharimide and its cytotoxicity on SK-Hep-1 hepatoma cells, Bioorg. Med. Chem. Lett. 17 (2007) 1155-1159. [186] W.X. Cai, A.L. Liu, Z.M. Li, W.L. Dong, X.H. Liu, N.B. Sun, Synthesis and anticancer activity of novel thiazole-5-carboxamide derivatives, Appl. Sci. 6(8) (2016) 1-10. 109
[187] X. Liu, L. Deng, H. Song, H. Jia, R. Wang, Asymmetric aza-mannich addition: Synthesis of modified chiral 2-(ethylthio)-thiazolone derivatives with anticancer potency, Org. Lett. 13(6) (2011) 1494-1497. [188] X. Zeng, B. Yin, Z. Hu, C. Liao, J. Liu, S. Li, Z. Li, M.C. Nicklaus, G. Zhou, S. Jiang, Total synthesis and biological evaluation of largazole and derivatives with promising selectivity for cancers cells, Org. Lett. 12(6) (2010) 1368-1371. [189] X.H. Shi, Z. Wang, Y. Xia, T.H. Ye, M. Deng, Y.Z. Xu, Y.Q. Wei, L. Yu, Synthesis and biological evaluation of novel benzothiazole-2-thiol derivatives as potential anticancer agents, Molecules 17 (2012) 3933-3944. [190] Y.N. Mabkhot, A. Barakat, A.M. Al-Majid, S. Alshahrani, S. Yousuf, M.I. Choudhary, Synthesis, reactions and biological activity of some new bis-heterocyclic ring compounds containing sulphur atom, Chem. Cent. J. 7(112) (2013) 1-9. [191] Y.X. Li, X. Zhai, W.K. Liao, W.F. Zhu, Y. He, P. Gong, Design, synthesis and biological evaluation of new rhodacyanine analogues as potential antitumour agents, Chin. Chem. Lett. 23 (2012) 415-418. [192] Y. Luo, F. Xiao, S. Qian, W. Lu, B. Yang, Synthesis and in vitro cytotoxic evaluation of some thiazolylbenzimidazole derivatives, Eur. J. Med. Chem. 46 (2011) 417-422. [193] Y. Matsuya, T. Kawaguchi, K. Ishihara, K. Ahmed, Q. Zhao, T. Kondo, H. Nemoto, Synthesis of macrosphelides with a thiazole side chain, New antitumour candidates having apoptosis-inducing property, Org. Lett. 20(6) (2006) 4609-4612. [194] Y. Kanda, T. Ashizawa, K. Kawashima, S. Ikeda, T. Tamaoki, Synthesis and antitumour activity of novel C-8 ester derivatives of leinamycin, Bioorg. Med. Chem. Lett. 13 (2013) 455-458. [195] M. Chakrabarty, T. Kundu, S. Arima, Y. Harigaya, An expedient, regioselective synthesis of novel 2-alkylamino- and 2-alkylthiothiazolo[5,4-e]- and -[4,5-g]indazoles and their anticancer potential, Tetrahedron 64 (2008) 6711-6723. [196] M.V. de Oliveira Cardoso, D.R.M. Moreira, G.B. Oliveira Filhoa, S.M.T. Cavalcanti, L.C.D. Coelho, J.W.P. Espindol, L.R. Gonzalez, M.M. Rabello, M.Z. Hernandes, P.M.P. Ferreira, C. Pessoad, C.A. de Simonee, E.T. Guimarae, M.B.P. Soares, A.C. LimaLeite, Design, synthesis and structure-activity relationship of phthalimides endowed with dual antiproliferative and immunomodulatory activities, Eur. J. Med. Chem. 96 (2015) 491503.
110
[197] M.I.L. Soares, A.F. Brito, M. Laranjo, A.M. Abrantes, M.F. Botelho, J.A. Paixao, A.M. Beja, M.R. Silva, M.V.D. Teresa, P. Melo, Chiral 6-hydroxymethyl-1H,3H-pyrrolo[1,2c]thiazoles: Novel antitumour DNA monoalkylating agents, Eur. J. Med. Chem. 45 (2010) 4676-4681. [198] A. Carbone, B. Parrino, G.V. Vita, A. Attanzio, V. Spano, A. Montalbano, P. Barraja, L. Tesoriere, M.A. Livrea, P. Diana, G. Cirrincione, Synthesis and antiproliferative activity of thiazolyl-bis-pyrrolo[2,3-b]pyridines and indolyl-thiazolyl-pyrrolo[2,3-c]pyridines, nortopsentin analogues, Mar. Drugs 13 (2015) 460-492. [199] B. Parrino, A. Carbone, G.D. Vita, C. Ciancimino, A. Attanzio, V. Spano, A. Montalbano, P. Barraja, L. Tesoriere, M.A. Livrea, P. Diana, G. Cirrincione, 3-[4-(1H-Indol-3-yl)-1,3thiazol-2-yl]-1H-pyrrolo[2,3-b]pyridines, nortopsentin analogues with antiproliferative activity, Mar. Drugs 13 (2015) 1901-1924. [200] R. Sadashiva, D. Naral, J. Kudva, S.M. Kumar, K. Byrappa, M.R. Shafeeulla, M. Kumsi, Synthesis, structure characterization, in vitro and in silico biological evaluation of a new series of thiazole nucleus integrated with pyrazoline scaffolds, J. Mol. Structure 1145 (2017) 18-31. [201] S. Mirza, S.A. Naqvi, K.M. Khan, U. Salar, M.I. Choudhary, Facile synthesis of novel substituted aryl-thiazole (SAT) analogs via onepot multi-component reaction as potent cytotoxic agents against cancer cell lines, Bioorg. Chem. 70 (2017) 133-143. [202] M. Popsavin, S. Spaic, M. Svircev, V. Kojic, G. Bogdanovic, V. Popsavina, Synthesis and antitumour activity of new tiazofurin analogues bearing a 2,3-anhydro functionality in the furanose ring, Bioorg. Med. Chem. Lett. 17 (2007) 4123-4127. [203] M.A. Abdelgawad, A. Belal, O.M. Ahmed, Synthesis, molecular docking studies and cytotoxic screening of certain novel thiazolidinone derivatives substituted with benzothiazole or benzoxazole, J. Chem. Pharm. Res. 5(2) (2013) 318-327. [204] H. He, X. Wang, L. Shi, W. Yin, Z. Yang, H. He, Y. Liang, Synthesis, antitumour activity and mechanism of action of novel 1,3-thiazole derivatives containing hydrazide-hydrazone and carboxamide moiety, Bioorg. Med. Chem. Lett. 26 (2016) 3263-3270. [205] S.M. Gomha, K.D. Khalil, A convenient ultrasound-promoted synthesis of some new thiazole derivatives bearing a coumarin nucleus and their cytotoxic activity, Molecules 17 (2012) 9335-9347. [206] S.M. Gomha, S.A. Ahmed, A.O. Abdelhamid, Synthesis and cytotoxicity evaluation of some novel thiazoles, thiadiazoles, and pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidin5(1H)-ones incorporating triazole moiety, Molecules 20 (2015) 1357-1376. 111
[207] S.M. Gomha, Y.H. Zaki, A.O. Abdelhamid, Utility of 3-acetyl-6-bromo-2H-chromen-2one for the synthesis of new heterocycles as potential antiproliferative agents, Molecules 20 (2015) 21826-21839. [208] S.M. Gomha, T.A. Salaheldin, H.M.E. Hassaneen, H.M. Abdel-Aziz, M.A. Khedr, Synthesis, characterization and molecular docking of novel bioactive thiazolyl-thiazole derivatives as promising cytotoxic antitumour drug, Molecules 21(3) (2016) 1-17. [209] M.M. Ghorab, D.A.A. El Ella, H.I. Heiba, A.M. Soliman, Synthesis of certain new thiazole derivatives bearing a sulfonamide moiety with expected anticancer and radiosensitizing activities, J. Materials Sci. Eng. A1 (2011) 684-691. [210] M.M. Ramla, M.A. Omar, H. Tokuda, H. El-Diwania, Synthesis and inhibitory activity of new benzimidazole derivatives against Burkitt’s lymphoma promotion, Bioorg. Med. Chem. 15 (2007) 6489-6496. [211] V. Gududuru, E. Hurh, J.T. Dalton, D.D. Miller, Synthesis and antiproliferative activity of 2-aryl-4-oxo-thiazolidin-3-yl-amides for prostate cancer, Bioorg. Med. Chem. Lett. 14 (2004) 5289-5293. [212] T. Tzanova, M. Gerova, O. Petrov, M. Karaivanova, D. Bagrel, Synthesis and antioxidant potential of novel synthetic benzophenone analogues, Eur. J. Med. Chem. 44 (2009) 27242730. [213] K. Saravanan, R. Elancheran, S. Divakar, S.A.A. Anand, M. Ramanathan, J. Kotoky, N.K. Lokanath, S. Kabilan, Design, synthesis and biological evaluation of 2-(4-phenylthiazol-2yl) isoindoline-1,3-dione derivatives as anti-prostate cancer agents, Bioorg. Med. Chem. Lett. 27 (2017) 1199-1204. [214] M.M. Ghorab, M.S. Alsaid, A.A. Shahat, Synthesis of some sulfonamide incorporating enaminone,
quinolone
moieties
and
thiazoloquinazoline
derivative
induce
the
cytoprotective enzyme NAD(P)H: Quinone oxidoreductase, Biomed. Res. 27(3) (2016) 695-701. [215] F.S.A. Rahman, S.K. Yusufzai, H. Osman, D. Mohamad, Synthesis, characterisation and cytotoxicity activity of thiazole substitution of coumarin derivatives (characterisation of coumarin derivatives), J. Physical Sci. 27(1) (2016) 77-87. [216] V. Pejchal, S. Stepankova, M. Pejchalova, K. Kralovec, R. Havelek, Z. Ruzickova, H. Ajani, R. Lo, M. Lepsik, Synthesis, structural characterization, docking, lipophilicity and cytotoxicity of 1-[(1R)-1-(6-fluoro-1,3-benzothiazol-2-yl)ethyl]-3-alkyl carbamates, novel acetylcholinesterase and butyrylcholinesterase pseudo-irreversible inhibitors, Bioorg. Med. Chem. 24 (2016) 1560-1572. 112
[217] A. Grozav, O. Balacescu, L. Balacescu, T. Cheminel, I. Berindan-Neagoe, B. Therrien, Synthesis, anticancer activity, and genome profiling of thiazolo arene ruthenium complexes, J. Med. Chem. 58 (2015) 8475-8490. [218] K.Z. Laczkowski, M. Switalska, A. Baranowska-Lczkowska, T. Plech, A. Paneth, K. Misiura, J. Wietrzyk, B. Czaplinska, A. Mrozek-Wilczkiewicz, K. Malarz, R. Musioł, I. Grela, Thiazole-based nitrogen mustards: Design, synthesis, spectroscopic studies, DFT calculation, molecular docking, and antiproliferative activity against selected human cancer cell lines, J. Mol. Structure 1119 (2016) 139-150. [219] Z.L. Wu, Y.L. Fang, Y.T. Tang, M.W. Xiao, J. Ye, G.X. Lia, A.X. Hu, Synthesis and antitumour evaluation of 5-(benzo[d][1,3]dioxol-5-ylmethyl)-4-(tert-butyl)-N-arylthiazol2-amines, Med. Chem. Comm. 7 (2016) 1768-1774. [220] L. Balanean, C. Braicu, I. Berindan-Neagoe, C. Nastasa, B. Tiperciuc, P. Verite, O. Oniga, Synthesis of novel 2-metylamino-4-substituted-1,3-thiazoles with antiproliferative activity, Rev. Chim. 65(12) (2014) 1413-1417. [221] K.K. Bansal, D. Sharma, A. Sharma, H. Rajak, P.C. Sharma, Novel thiazole clubbed triazole derivatives as antimicrobial, antimalarial and cytotoxic agents. Indian J. Heterocycl. Chem. 28(2) (2018) 305-312. [222] P. Sharma, T.S. Reddy, D. Thummuri, K.R. Senwar, N.P. Kumar, V.G.M. Naidu, S.K. Bhargava, N. Shankaraiah, Synthesis and biological evaluation of new benzimidazolethiazolidinedione hybrids as potential cytotoxic and apoptosis inducing agents, Eur. J. Med. Chem. 124 (2016) 608-621. [223] F. Tay, C. Erkan, N.Y. Sariozlu, E. Ergene, S. Demirayak, Synthesis, antimicrobial and anticancer activities of some naphthylthiazolylamine derivatives, Biomed. Res. 28(6) (2017) 2696-2703. [224] S.M. Gomha, N.A. Kheder, M.R. Abdelaziz, Y.N. Mabkhot, A.M. Alhajoj, A facile synthesis and anticancer activity of some novel thiazoles carrying 1,3,4-thiadiazole moiety, Chem. Cent. J. 11 (2017) 25. [225] J. Park, M.I. El-Gamal, Y.S. Lee, C. Oh, New imidazo[2,1-b]thiazole derivatives: Synthesis, in vitro anticancer evaluation, and in silico studies, Eur. J. Med. Chem. 46 (2011) 5769-5777. [226] J. Park, C. Oh, Synthesis of new 6-(4-fluorophenyl)-5-(2-substituted pyrimidin-4-yl) imidazo [2, 1-b] thiazole derivatives and their antiproliferative activity against melanoma cell line, Bull. Korean Chem. Soc. 31(10) (2010) 2854-2860.
113
[227] Y. Liang, Z. Yue, J. Li, C. Tan, Z. Miao, W. Tan, C. Yang, Natural product-based design, synthesis and biological evaluation of anthra[2,1-d]thiazole-6,11-dione derivatives from rhein as novel antitumour agents, Eur. J. Med. Chem. 84 (2014) 505-515. [228] K. Santos, M. Laranjo, A.M. Abrantes, A.F. Brito, C. Gonçalves, A.B.S. Ribeiro, F.M. Botelho, M.I.L. Soares, A.S.R. Oliveira, T. Pinho Melo, Targeting triple-negative breast cancer cells with 6,7-bis(hydroxymethyl)-1H,3H-pyrrolo[1,2-c]thiazoles, Eur. J. Med. Chem. 79 (2014) 273-281. [229] V. Zaharia, A. Ignat, N. Palibroda, B. Ngameni, V Kuete, C.N. Fokunang, M.L. Moungang, B.T. Ngadjui, Synthesis of some p-toluenesulfonyl-hydrazinothiazoles and hydrazino-bisthiazoles and their anticancer activity, Eur. J. Med. Chem. 45 (2010) 50805085. [230] L. Shao, X. Zhou, Y. Hu, Z. Jin, J. Liu, J. Fang, Synthesis and evaluation of novel ferrocenyl thiazole derivatives as anticancer agents. Synthesis and Reactivity in Inorganic, Metal-Organic and Nano-Metal Chem. 36 (2006) 325-330. [231] G. Sadhasivam, K. Kulanthai, A. Natarajan, Synthesis and anti-cancer studies of 2, 6disubstituted benzothiazole derivatives, Orient. J. Chem. 31(2) (2015) 819-826. [232] M.D. Altintop, A. Ozdemir, G. Turan-Zitouni, S. Ilgin, O. Atli, R. Demirel, Z.A. Kaplancikli, A novel series of thiazolyl-pyrazoline derivatives: Synthesis and evaluation of antifungal activity, cytotoxicity and genotoxicity, Eur. J. Med. Chem. 92 (2015) 342352. [233] M.J. Gorczynski, R.M. Leal, S.L. Mooberry, J.H. Bushwellera, M.L. Browna, Synthesis and evaluation of substituted 4-aryloxy- and 4-arylsulfanyl-phenyl-2-aminothiazoles as inhibitors of human breast cancer cell proliferation, Bioorg. Med. Chem. 12 (2004) 10291036. [234] A. Andreani, S. Burnelli, M. Granaiola, A. Leoni, A. Locatelli, R. Morigi, M. Rambaldi, L. Varoli, N. Calonghi, C. Cappadone, G. Farruggia, M. Zini, C. Stefanelli, L. Masotti, N. S. Radin, R.H. Shoemaker, New antitumour imidazo[2,1-b]thiazole guanylhydrazones and analogues, J. Med. Chem. 51(4) (2008) 809-816. [235] A. Andreani, M. Granaiola, A. Leoni, A. Locatelli, R. Morigi, M. Rambaldi, G. Lenaz, R. Fato, C. Bergamini, G. Farruggia, Potential antitumour agents. 37. Synthesis and antitumour activity of guanylhydrazones from imidazo[2,1-b]thiazoles and from the new heterocyclic system thiazolo[2‘,3‘:2,3]imidazo[4,5-c]quinolone, J. Med. Chem. 48(8) (2005) 3085-3089.
114
[236] M. Popsavin, L. Torovic, M. Svircev, V. Kojic, G. Bogdanovic, V. Popsavina, Synthesis and antiproliferative activity of two new tiazofurin analogues with 20-amido functionalities, Bioorg. Med. Chem. Lett. 16 (2006) 2773-2776. [237] S.M. Gomha, A.O. Abdelhamid, N.A. Abdelrehem, S.M. Kandeel, Efficient synthesis of new benzofuran-based thiazoles and investigation of their cytotoxic activity against human breast carcinoma cell lines, J. Heterocycl. Chem. 55(4) 2018 995-1001. [238] S.M. Gomha, M.R. Abdelaziz, N.A. Kheder, H.M. Abdel-Aziz, S. Alterary, Y.N. Mabkhot, A facile access and evaluation of some novel thiazole and 1, 3, 4-thiadiazole derivatives incorporating thiazole moiety as potent anticancer agents, Chem. Cent. J. 11(1) (2017) 105. [239] T.D. Dos Santos Silva, L.M. Bomfim, A.C.B. da Cruz Rodrigues, R.B. Dias, C.B.S. Sales, C.A.G. Rocha, M.B.P. Soares, D.P. Bezerra, M.V. de Oliveira Cardoso, A.C.L. Leite, G.C.G. Militao, Anti-liver cancer activity in vitro and in vivo induced by 2-pyridyl 2, 3thiazole derivatives, Toxicol. Appl. Pharmacol. 329 (2017) 212-223. [240] P.K.N. Sarangi, J. Sahoob, S. Beherac, S.K. Paidesetty, G.P. Mohantae, Cytotoxic investigation of some newly synthesized quinoline-thiazole based azo compounds, Indian J. Chem. 56B (2017) 1256-1264. [241] R. Xu, Y. Tian, S. Huang, J. Yu, Y. Deng, M. Zhan, T. Zhang, F. Wang, L. Zhao, Y. Chen, Synthesis and evaluation of novel thiazole-based derivatives as selective inhibitors of DNA-binding domain of the androgen receptor, Chem. Biol. Drug Des. 91(1) (2018) 172-180. [242] E. Abdel-Latif, E.M. Keshk, A. Saeed, A.M. Khalil, Synthesis and anticancer evaluation of some new heterocyclic scaffolds incorporating the acetanilide moiety, Modern Org. Chem. Res. 2(3) (2017) 112-123. [243] R.M. Mohareb, A.E.M. Abdallah, A.A. Mohamed, Synthesis of novel thiophene, thiazole and coumarin derivatives based on benzimidazole nucleus and their cytotoxicity and toxicity evaluations, Chem. Pharm. Bull. 66 (2018) 309-318. [244] A. Ahamed, I.A. Arif, M. Mateen, R.S. Kumar, A. Idhayadhulla, Antimicrobial, anticoagulant, and cytotoxic evaluation of multidrug resistance of new 1,4dihydropyridine derivatives, Saudi J. Biol. Sci. 25(6) (2018) 1227-1235. [245] S.M. Gomha, M.M. Edrees, F.M.A. Altalbawy, Synthesis and characterization of some new bis-pyrazolyl-thiazoles incorporating the thiophene moiety as potent anti-tumour agents, Int. J. Mol. Sci. 17 (2016) 1499.
115
[246] C. Ge, L. Chang, Y. Zhao, C. Chang, X. Xu, H. He, Y. Wang, F. Dai, S. Xie, C. Wang, Design, synthesis and evaluation of naphthalimide derivatives as potential anticancer agents for hepatocellular carcinoma, Molecules 22 (2017) 342. [247] M.P. Tantak, J. Wang, R.P. Singh, A. Kumar, K. Shah, D. Kumar, 2-(3’-Indolyl)-Narylthiazole-4-carboxamides: Synthesis and evaluation of antibacterial and anticancer activities, Bioorg. Med. Chem. Lett. 25 (2015) 4225-4231. [248] K. Vaarla, R.K. Kesharwani, K. Santosh, R.R. Vedula, S. Kotamraju, M.K. Toopurani, Synthesis, biological activity evaluation and molecular docking studies of novel coumarin substituted thiazolyl-3-aryl-pyrazole-4-carbaldehydes, Bioorg. Med. Chem. Lett. 25 (2015) 5797-5803. [249] A. Leoni, A. Locatelli, R. Morigi, M. Rambaldi, Novel thiazole derivatives: A patent review (2008-2012. Part 2), Expert Opin. Ther. Pat. 24(7) (2014) 759-777. [250] P. Mei, S. Kun, L. Ying, H. Aixi, Application of 5-(2-nitro ethyl) thiazole derivatives as anticancer drug, CN105078977, A, November 25, 2015. [251] G. Wang, Q. Jiang, Q. Zhong, Q. Zhang, S. Zheng, Anti-migration and anti-invasion thiazole analogs for treatment of cellular proliferative disease, US 20150274714 A1, October 1, 2015. [252] S. Han, Y.S. Kim, J.T. Hong, N. Nam, D.N. Mai, D.T. Phuong, O.T. Kim, Novel phenylthiazole-based hydroxamic acid and anti-cancer composition containing same as active ingredient, WO2015016442, A1, February 5, 2015. [253] J. Lajeunesse, J.D. DiMarco, E. Brunswick, M. Galella, R. Chidambaram, Process for preparing 2-aminothiazole-5-aromatic carboxamides as kinase inhibitors, US 8,680,103 B2, March 25, 2014. [254] M. Dumble, T. Gilmer, R. Kumar, P.F. LeboWitz, S.R. Morris, S. Laquerre, Combination of a B-RAF inhibitor: N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol4-yl]-2fluorophenyl}2,6-difluorobenzenesulfonamide and the Akt inhibitor: N-{(1s)-2 amino-1-[(3- fluorophenyl) methyl]ethyl}-5-chioro-4-(4-chioro 1-methyl-1H-pyrazol-syl)-2-10 thiophenecarboxamide useful in the treatment of cancer, US 8,796,298 B2, August 5, 2014. [255] M. Mortimore, J. Golec, C. Davis, D. Robinson, J. Studley, Thiazoles and pyrazoles useful as kinase inhibitors, US 8,785,444 B2, July 22, 2014. [256] P.P. Beroza, K.V. Damodaran, E. Laborde, W. Thomas, Substituted thiazoles as VEGFR2 kinase inhibitors, US 2013/0184280 A1, July 18, 2013.
116
[257]
J. Song, Method of cancer treatment with 2-(1H-indole-3-carbonyl)-thiazole-4 carboxylic acid methyl ester, US 2013/0338201 A1, December 19, 2013.
[258] G. W. Shipps, M. Richards, C.C. Cheng, X. Huang, Thiazole carboxamide derivatives and their use to treat cancer, US 8,394,960 B2, March 12, 2013. [259] K. Uoto, Y. Sugimoto, H. Naito, M. Mlyazaki, K. Yoshida, M. Aonuma, Imidazothiazole derivatives having proline ring structure, US 8,404,691 B2, March 26, 2013. [260]
T. Irie, M. Sawa, S. Ito, C. Tanaka, S.G. Ro, H.C. Park, Thiazolidinone derivatives, US 8,119,812, B2, February 21, 2012.
[261] A. Hamed, B. Christoph, B. Christine, G. Markus, G. John, S. Romain, S. Thierry, T.W. Jodi, Thiazolidin-4-one and [1,3]-thiazinan-4-one compounds as orexin receptor antagonists, US 2012/0088759 A1, April 12, 2012. [262] H. An, B. Xi, Y. Abassi, X. Wang, X. Xiao, Imidazothiazole-chalcone derivatives as potential heterocyclic compounds and uses as anticancer agents, US 8,252,822 B2, August 28, 2012. [263] M. Mortimore, J. Golec, C. Davis, D. Robinson, J. Studley, Thiazoles and pyrazoles useful as kinase inhibitors, US 8,268,811 B2, September 18, 2012. [264] T. Irie, M. Sawa, S. Ito, C. Tanaka, S.G. Ro, H.C. Park, Thiazolidinone derivatives, U.S. Patent US 0190299, A1, August 4, 2011. [265] M.P. Mortimore, C.J. Davis, J.M.C. Golec, J. Studley, D.D. Robinson, Thiazoles and pyrazoles useful as kinase inhibitors, US 2011/0060013 A1, March 10, 2011. [266] D. Romo, J. Liu, N.S. Choi, Z. Shi, W. Low, Y. Dang, T. Schneider-Poetsch, Anticancer agents and use, US 7,737,134 B2, June 15, 2010. [267] D.D. Miller, J.T. Dalton, V. Gududuru, E. Hurh, (4R)-2-(4-methoxyphenyl)-Noctadecylthiazolidine-4-carboxamide; Antiacarcinogenic agent for destroying a melanoma cell, US 7,662,842, B2, February 16, 2010. [268] J. Lajeunesse, J.D. DiMarco, M. Galella, R. Chidambaram, Process for preparing 2aminothiazole-5-aromatic carboxamides as kinase inhibitors, US 7,491,725 B2, February 17, 2009. [269] C. Mara, C. Gennaro, D.M. Sergio, G. Mario, Use of thiazolidinone derivatives as antiangiogenic agents, US 0261980, A1, October 23, 2008. [270] S.M. Courtney, P.A. Hay, D.I.C. Scopes, Novel furanthiazole derivatives which are useful as inhibitors of heparanase, US 7,326,727 B2, February 5, 2008. [271] G. Siemeister, H. Briem, V. Schulze, K. Eis, L. Wortmann, W. Schwede, H. Schneider, V. Eberspaecher, H.H. Stumpp, Inhibitors of polo-like kinases; (4,4-dimethyl-4,5-dihydro117
oxazol-2-yl)-[3-ethyl-4-oxo-5-[1-[3-(2-pyrrolidin-1-yl-ethyl)-phenylamino]-meth-(E/Z)ylidene]-thiazolidin-(2-(E or Z))-ylidene]-acetonitrile; cancer, auto-immune diseases, cardiovascular diseases, US 0037862, A1, February 15, 2007. [272] B. Lippa, Mystic, A. Kwan, J. Morris, S.D. LaGreca, M.D. Wessel, Novel isothiazole derivatives that are useful in the treatment of hyperproliferative diseases, US 7,276,602 B2, October 2, 2007. [273] W. SchWede, V. Schulze, K. Eis, B. Buchmann, H. Briem, G. Siemeister, U. Boemer, K. Parczyk, Thiazolidinones and the use therof as polo-like kinase inhibitors, US 0079503, A1, April 13, 2006. [274] M. Pfahl, C. Tachdjian, T.R. Wiemann, N.C. Christopher, L.W. Spruce, A.F. Giachino, A.A. Kaspar, J.W. Zapf. Benzoxazole, benzothiazole, and benzimidazole derivatives for the treatment of cancer and other diseases, US 2005/0014767 A1, January 20, 2005. [275] E.W. Yue, Novel 3-(2, 4 dimethylthiazol-5-yl)indeno[1,2-c]pyrazol-4-one derivatives which are useful as cyclin dependent kinase (Cdk) inhibitors, US 6,706,718 B2, March 16, 2004. [276] J.J.V. Duncia, D.S. Gardner, J.O.B Santella, N-adamant-1-y1-N1-[4 chlorobenzothiazol-2y1] urea useful in the treatment of inflammation and as an anticancer radiosensitizing agent, US 6,214,851 B1, April 10, 2001. [277] E. Albert, E. Bacque, C. Nemecek, A. Ugolini, S. Wentzler, 6-Triazolopyridazine sulfanyl benzothiazole derivatives as MET inhibitors, US 9,321,777 B2, April 26, 2016. [278] R. Roziev, A. Goncharova, K.T. Erimbetov, V. Podgorodnichenko, V. Khomichenok, N. Novozhilova, Agent for the prophylaxis and/or treatment of neoplastic diseases, US 20160038472, A1. February 11, 2016. [279] R.J. Boohaker, M.W. Lee, P. Vishnubhotla, J.M. Perez, A.R. Khaled. The use of therapeutic peptides to target and to kill cancer cells, Curr. Med. Chem. 19(22) (2012) 3794-3804. [280] Y. Xiao, M. Jie, B. Li, C. Hu, R. Xie, B. Tang, S. Yang. Peptide-based treatment: A promising cancer therapy. J. Immun. Res. (2015) 1-13 Article ID 761820. [281] J. Thompson, E. Cundliffe, M.J.R. Stark, The mode of action of berninamycin and the mechanism of resistance in the producing organism, Streptomyces bernensis, J. Gen. Microb. 128 (1982) 815-884. [282] A. Ninomiya, S. Kodani, Isolation and identification of berninamycin A from Streptomyces atroolivaceus, NPAIJ. 7(4) (2011) 163-167.
118
[283] E. Cundliffe, J. Thompson, Concerning the mode of action of micrococcin upon bacterial protein synthesis, Eur. J. Biochem. 118 (1981) 47-52. [284] X. Just-Baringo, F. Albericio, M. Alvarez, Thiopeptide antibiotics: retrospective and recent advances, Mar. Drugs 12 (2014) 317-351. [285] https://www.google.com/patents/WO2002102400A1?cl=en [accessed on 14.05.2017] [286] L.C.W. Brown, M.G. Acker, J. Clardy, C.T. Walsh, M.A. Fischbach, Thirteen posttranslational modifications convert a 14-residue peptide into the antibiotic thiocillin, PNAS. 106(8) (2009) 2549-2553. [287] S. Kim, Use of macrocyclic peptide compound as anticancer agents and method for diagnosing cancer, Patent WO 2002102400 A1, June 14, 2002. [288] http://www.google.ch/patents/WO2002066046A1?cl=en. [accessed on 14.05.2017].
119
Highlights: •
Drugs containing 1,3-thiazole scaffold are having clinical applications in anticancer drug therapies.
•
Diverse biological targets and their potent inhibitors related to anticancer actions of thiazoles have been described.
•
Thiazole-containing compounds are important in enzyme inhibition including enzyme-linked receptors located on the cell membrane and the cell cycle.
•
A large number of compounds were cytotoxic against several cancer cell lines.
•
Brief summary of recent patents and novel cyclic peptide antibiotics in cancer treatment has been provided.
Declaration of interests √ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Authors declare no conflict of interest. The authors alone are responsible for the content and writing of the paper.
S0223-5234(19)31174-2
DOI:
https://doi.org/10.1016/j.ejmech.2019.112016
Reference:
EJMECH 112016
To appear in:
European Journal of Medicinal Chemistry
Received Date: 4 November 2019 Revised Date:
20 December 2019
Accepted Date: 26 December 2019
Please cite this article as: P.C. Sharma, K.K. Bansal, A. Sharma, D. Sharma, A. Deep, Thiazolecontaining compounds as therapeutic targets for cancer therapy, European Journal of Medicinal Chemistry (2020), doi: https://doi.org/10.1016/j.ejmech.2019.112016. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Masson SAS.
Thiazole-containing compounds as therapeutic targets for cancer therapy Prabodh Chander Sharma*a, Kushal Kumar Bansala, Archana Sharmaa, Diksha Sharmaa, Aakash Deepb a
Institute of Pharmaceutical Sciences, Kurukshetra University, Kurukshetra, HR-136119,
India b
Department of Pharmaceutical Sciences, Chaudhary Bansi Lal University, Biwhani-127021,
India Graphical Abstract S
O R2 N
N S
R1 NH
N O
O
CH3
O
O S Cl
N
Cl
Cl
CF3
N S
N
Carbonic Anhy. Inhibitor
N
S N
O S H 2N O
R3
OH
S
N
HO O
O NH HN
N O
S
O
S
N
N
YX
B N
N
A
H2N N
S
S
H3CO
OCH3
OCH3
R
Tubulin Polymerase Inhibitor
NH2
H3CO
Monoacylglycerol lipase Inhibitor
N NH
S
N
N H
CH
Cl
R2
HN N
F N
N
DNA Intercalating Agents
R1
O
S
H N
S N N
S N CH3
S
O
N
N
S
R3
Ar HC N
R1 N N H
N N
N
N N HN
S
R2
H N
S O
Thiazoles as Multi-targeting Agents in Cancer
Cl
Cl
O S N
HO
N
N
NH2
N
NH2
HN
R2 R1
S
F
N H
Cl
Thiazole-containing compounds as therapeutic targets for cancer therapy Prabodh Chander Sharma* a, Kushal Kumar Bansala, Archana Sharmaa, Diksha Sharmaa, Aakash Deepb a
Institute of Pharmaceutical Sciences, Kurukshetra University, Kurukshetra, HR-136119,
India b
Department of Pharmaceutical Sciences, Chaudhary Bansi Lal University, Biwhani-127021,
India Abstract In the last few decades, considerable progress has been made in anticancer agents development, and several new anticancer agents of natural and synthetic origin have been produced. Among heterocyclic compounds, thiazole, a 5-membered unique heterocyclic motif containing sulphur and nitrogen atoms, serves as an essential core scaffold in several medicinally important compounds. Thiazole nucleus is a fundamental part of some clinically applied anticancer drugs, such as dasatinib, dabrafenib, ixabepilone, patellamide A, and epothilone. Recently, thiazole-containing compounds have been successfully developed as possible inhibitors of several biological targets, including enzyme-linked receptor(s) located on the cell membrane, (i.e., polymerase inhibitors) and the cell cycle (i.e., microtubular inhibitors). Moreover, these compounds have been proven to exhibit high effectiveness, potent anticancer activity, and less toxicity. This review presents current research on thiazoles and elucidates their biological importance in anticancer drug discovery. The findings may aid researchers in the rational design of more potent and bio-target specific anticancer drug molecules. Keywords: Heterocycles, 1,3-Thiazoles, Biological targets, Cyclic peptides, Anticancer activity. *Corresponding Author Address: Institute of Pharmaceutical Science, Kurukshetra University, Kurukshetra, HR-136119, India; Contact: +91-94160-25460; E-mail: [email protected]
1
1
Introduction The abnormality in the control mechanism that governs stimulation or suppression in normal cells is the hallmark of cancer [1,2]. The process of carcinogenesis initiates in normal cells as a result of a shift in control mechanism that might be caused due to activation of oncogenes, an inadequate function of tumour suppressor genes and mutagenic factors. The later is also associated with mutations in genes which initiate carcinogenesis. These factors involve distinctive biochemical and oncogenic regulatory pathways (non-enzymatic proteins) [3]. Among oncogenic pathways, RAS and PI3K signaling pathways claimes a higher number of cancers as compared to other pathways. Besides, enzyme malfunctions can cause the accumulation of certain substances that may result in cancer diseases [4,5]. Moreover, cancer may associate to malfunctioning of DNA, RNA, enzymes and some other proteins. Being a carrier of genetic information as well as central to tumour genesis and pathogenesis, DNA is a major target for drug development [6]. Hence, these approaches are being recognized as the potential targets for cancer treatment and drug development. Recent studies revealed that targeted therapy has emerged as a promising approach for the development of selective anticancer agents. Among the different targeted therapies, angiogenesis inhibitors are important classes of drugs which focus on blocking the development of new blood vessels in tumour tissues [7-9]. Target specific anticancer drugs also include DNA intercalators, DNA synthesis inhibitors, transcription regulators, enzyme inhibitors and cancer cell targeting peptides etc. [6]. As per scientific data available, cancer is the second leading cause of death after heart disease in the USA. In 2018, an estimated 1,735,350 new incidences of cancer cases have been diagnosed and 6,09,640 cancer deaths are likely to occurs in the United States, on the top with 14,070 ovarian cancer deaths [10]. The inadequate merits of available anticancer drugs for example lack of selectivity, target specificity, toxicity and developing resistance has led to serious consequences. The radio- and chemotherapeutics are the present methods of treatment of cancer widely known to be characterized by a low therapeutic index [11,12]. Novel approaches targeting the specific molecular alterations that occur in tumour are being used in treatment and eradication of cancers. An ideal anticancer drug would eliminate cancer cells without harming normal tissues. Unfortunately, no currently available agents meet this criterion with a favourable therapeutic index [13]. Therefore, novel anticancer agents owning target specific advanced
2
mechanism of action with favourable therapeutic index are considered valuable in the field of oncology related drug discovery. 2
Thiazole-containing compounds endowed with anticancer activity The biological activity of compounds mainly depends on their molecular structures [14]. Heterocycles, such as azoles occupy a prominent place in current medicinal chemistry due to their wide range of applications in the fields of drug design and discovery [15,16]. Their utility in different areas of medicine, particularly as potential anticancer drugs is being investigated. In recent years, thiazole, a five membered sulphur and nitrogen containing heterocyclic ligand has endorsed considerable interest due to their effective biological properties [17,18]. Thiazole and its derivatives are amongst most active classes of compounds that are known for their broad spectrum of activity e.g. antibacterial activity [19], antifungal activity [20], antimalarial activity [21], antitubercular activity [22], antiviral activity [23], anti-inflammatory activity [24], antidiabetic activity [25], anthelmintic activity [26], anticonvulsant activity [27], antioxidant activity [28], anticancer activity [29] and cardiovascular activity [30], etc. Moreover, thiazole-containing compounds have marked their presence in number of clinically available anticancer drugs (Figure 1) such as, tiazofurin (1) (inhibitor of IMP dehydrogenase) [31], dasatinib (2) (Bcr-Abl tyrosine kinase inhibitor) [32], dabrafenib (3) (inhibitor of enzyme B-RAF) [33], patellamide A (4) (cytotoxicity against multidrug resistant cancer) [34], ixabepilone (5) (stabilization of microtubules) [35], and epothilone (6) (inhibition of microtubule function) [36]. Thiazolecontaining compounds depict anticancer activity profile through diverse mechanisms. Figure 2 presents some of the most potent anticancer compounds bearing thiazole scaffold reported in different scientific studies [37-47]. In view of our continous interest [48-56] in anticancer activity of heterocyclic compounds and thiazole-containing compounds, we have attempted to review various aspects related to anticancer potential of thiazole-containing compounds.
3
5
Tiazofurin - inhibitor of IMP dehydrogenase Dasatinib - Bcr-Abl tyrosine kinase inhibitor Dabrafenib - Inhibitor of enzyme B-Raf
Ixabepilone - stabilization of microtubules Epothilone - inhibition of microtubule function Patellamide A - cytotoxicity against multidrug resistant cancer
S1
4
2
N 3
Thiazole
O
S
HO
N CH3
O
HO
N
N
H N
S
Cl
(1) Tiazofurin
N H
(2) Dasatinib
N
O
N H
N
N
CH3 CH3
HN N
O H N
N O H3C
S
S N
F (3) Dabrafenib
O CH3
S
S
N
(4) Patellamide A
CH3 O
O CH3
O
H3C
NH2
N
H3C
HN
HO H3C O
CH3
N
CH3
O
NH
H3C
N
O S O
H3C
H3C H3C
N
F
H N
OH
H3C H3C O
S
F
N
O
OH
CH3
H3C
CH3
NH2
CH3 CH3 OH
(5) Ixabepilone
O
O
R HO H3C O
CH3
H3C
CH3 OH
(6a,b) Epothilone 6a; (R=H) Epothilone 6b; (R=CH3)
Figure 1: Some clinically used thiazole-cotaining anticancer drugs. The anticancer activity of the compounds through inhibition of various enzymes, miscellaneous targets and cytotoxicity evaluation has been described (Section 2). A brief glimpse on recent patents filed/granted has also been provided (Section 3). Moreover, some selected natural compounds containing thiazole in clinical stage of drug discovery have also been specifically described (Section 4).
4
F
Cl
N
F F
Cl N Cl
S
F
N N N
H N
O
IC50; 5.48-17.80 µM (9)
S
O
O
S
N
O
Anti EGFR IC50; 0.06 µM (10)
HN
Cl HN N
IC50; 0.008-0.025 µM (8)
A2
A3
N
O
NCN
S Anti HAT IC50; 2 µM
S
N
O S
N
O
A1
(11)
IC50; 0.020-0.06 µM
A1, A2, A3 STRUCTURAL MODIFICATIONS
Br
(7) Cl
S N HN
N O
O
NO2 O O
Cl
Key Features
IC50; 8.28-41.48 µM (12)
N S
Cl
S N H
HN N
N S
NH NH IC50; 0.08 µM (14)
N H
IC50; 10.1-25 µM (13)
S
Br
1) Cyanoimine (N-CN) linkage at 4-thiazole showed promising in vitro anticancer activity in compound 7, replacement of cyanoimine (N-CN) linkage with carbonyl (C=O) along with 5-indolyl in compound 8 leads to better profile. 2) Electron withdrawing groups on phenyl ring, such as mono or bi- substituted with F and Cl i.e. compound 9 exhibited significant anticancer activity. 3) Thiazole based pyrazoline derivative (compound 10) possessed promising EGFR kinase inhibitory activity. 4) The existence of thiourea/hydrazine moiety on 2nd position of thiazole seems to exhibit a very good histone acetyl transferase enzyme inhibitory activity in compound 11, and significant cytotoxicity in compounds 13 & 14 5) In case of compound 12, a CONH linkage attached to thiazole nitrogen and para phenyl substitutions with halogen and nitro moieties, respectively demonstrated excellent cytotoxic activities.
Figure 2: Some representatives of thiazole-containing compounds endowed with potent anticancer activities. 2.1 Important enzymatic pathways in carcinogenesis Recently, enzyme inhibition has been identified as an alternative and significant target strategy for the treatment of tumours [57]. Thiazole-containing compounds have been reported effective in inhibiting a number of such enzymes/enzymatic pathways. A number of 5
risk factors lead to the molecular changes or mutations in some important proteins such as tyrosin kinases and initiate the carcinogenesis. These tyrosin kinases serve as important roles in normal cell proliferation, differentiation, cell survival, metabolism, cell migration, cellcycle control through the phosphorylation of tyrosine residues in proteins [58,59]. On the other hand, receptor tyrosine kinases (RTKs) represent high-affinity cell surface receptors that function in transmembrane signalling and play a transforming role in the plethora of cancers [60,61].
Figure 3: Intracelluar signailling pathways activated by tyrosin kinase receptors. Thiazole-containing compounds as small molecular inhibitors (in red lines). Abbreviations; EGF: Epidermal growth factor; EGFR: EGF receptor; CDK: cyclin-dependent kinase; PI3K: phosphatidylinositol 3-kinase; AKT: protein kinases B; RAS: Rat sarcoma subfamily of GTPases; MEK: mitogen-activated protein kinase kinase; mTOR: mammalian target of rapamycin; B-RAF: B-type RAF kinase; VEGF: vascular endothelial growth factor; VEGFR: VEGF receptor; src: v-Src (Rous sarcoma virus) tyrosine kinase; HAT: Histone acetylase; HDAC: histone deacetylases; NF-КB: protein complex (nuclear factor kappa-light-chain-enhancer of activated B cells).
Studies revealed that elevated levels of activated Akt, NF-КB, and HIF-1α in neoplastic cells are associated with an increased risk for cancer development [62]. These molecular pathways are also crucial regulators of the angiogenic process, a rate-limiting step in cancer progression and a rational target for tailoring cancer chemoprevention regimens [63,64]. Numerous drugs have been approved by United States Food and Drug Administration (FDA) for the treatment of cancer caused by activated RTKs [65]. Further, it has also been found that targeted therapy has appreciably improved the survival rate of the cancer patients. Monoclonal antibodies and 6
small-molecular inhibitors have been extensively studied and subjected for clinical trial that targets cancer cells. Interestingly, the small-molecular RTKs inhibitors affect multiple tyrosine kinases [66]. Monoclonal antibodies that bind to the extracellular domain of ErbB2 (trastuzumab/herceptin) or EGFR (cetuximab/erbitux and panitumumab/vectibix) have been successfully used to treat mammary carcinoma, colorectal cancer, and head and neck cancers, respectively. A new thiazole-containing anticancer drug dasatinib (sprycel) targets Abl, Arg, KIT, PDGFR, Src in the treatment of chronic myelogenous leukemia (CML) [67,68] and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). Recent scientific data reveals that thiazole containing compounds have significant potential in interfering and inhibiting the above dicussed enzyme targets as described in (Figure 3). Some important enzymes that play a vital role in cancer progress and intractions/inhibition of these biotargets by thiazole-containing compounds are described in following text. 2.1.1
EGFR kinase inhibitors The epidermal growth factor receptor (EGFR) is an earlier proposed target for cancer treatment. The increase in EGFR expression causes development of aggressive subtype of certain cancers such as triple-negative breast cancer (TNBC) [69]. Thiazoles in conjugation with heterocyclic compounds have been studied for their EGFR kinase inhibitory activity as potential antitumour agents. Recently, thiazolyl-pyrazoline derivatives were scrutinized by Lv et al. in order to explore their potential as EGFR kinase inhibitory activity. Compound (15a) displayed the most potent EGFR TK inhibitory activity with IC50 of 0.06 µM. Molecular docking results indicated that compound (15a) was bound to the EGFR kinase with three hydrogen bonds. Furthermore, this compound also displayed significant in vitro antiproliferative activity against MCF-7 with IC50 of 0.07 µM, which was comparable to standard drug erlotinib (IC50; 0.02 µM). All the test compounds (15a–15f) displayed good antiproliferative activity against MCF-7 with IC50 ranging from 0.16 to 1.47 µM. Hence, compound (15a) might be considered as valuable candidate for further chemical modifications [44]. Wang et al. evaluated novel thiazolyl-pyrazoline clubbed benzodioxole derivatives for their in vitro antiproliferative activity against HER-2 (EGFR family), MCF-7 (human breast cancer cell lines) and B16-F10 cells (mouse melanoma cell lines). Generally, the test compounds revealed good inhibition against both the cell lines MCF-7 and B16-F10 with IC50 values between 0.09 and 4.53 µM, 0.12 and 4.43 µM, respectively. From the series, compound (16) 7
bearing one bromine atom at para- position on phenyl ring exhibited the most potent inhibitory activity against HER-2 (EGFR family), MCF-7 (human breast cancer cell lines) and B16-F10 cells (mouse melanoma cell lines) with IC50; 0.18 µM for HER-2, IC50; 0.09 and 0.12 µM, respectively in comparison to the positive control erlotinib (IC50; 0.02-0.05 µM) [70]. Cytotoxic
activity
of
some
novel
N-pyridinyl-2-(6-phenylimidazo[2,1-b]thiazol-3-
yl)acetamide against two (HEPG2, MDA-MB-231) human cancer cell lines and inhibitory activity against VEGFR2 kinase was carried out by Ding et al. Results indicated that among the test compounds, compound (17) have showed VEGFR2 kinase inhibition at a rate of 5.72% (20 µM) and was a potent inhibitor against MDA-MB-231 (IC50; 1.4 µM), HEPG2 cell line (IC50; 22.6 µM) as compared to standard drug sorafenib (IC50; 5.2 µM). However, one compound (18) showed only 3.76% rate of inhibition on VEGFR2 kinase and exhibited reasonable cytotoxic activity against the HEPG2 and MDA-MB-231 cell lines which provides a potential hit lead for further investigation to be used as cytotoxic agent [71]. In another study, Lv et al. introduced two series of thiazolidinone derivatives and assayed for inhibitory action against EGFR and HER-2 kinases. Some of the synthesized compounds displayed potent EGFR and HER-2 inhibitory activities. Compound (19) displayed the most potent EGFR and HER-2 inhibitory activities (IC50; 0.09 µM for EGFR and IC50; 0.42 µM for HER-2) in MCF-7 cell lines as compared to erlotinib. The EGFR molecular docking model suggested that compound (19) have shown excellent binding on the hydroxyl group, also formed hydrogen bond projected towards the mercapto group of Met 769, side chain mercapto group of Cys 751, respectively [72]. Bhanushali et al. screened a novel series of 5-benzylidene-2,4-thiazolidinediones and evaluated in vitro VEGFR-2 kinase inhibitors in order to find out anti-angiogenesis activity. Compounds (20) and (21) demonstrated prominent inhibitory activity in CAM and zebrafish assay; and were selected for the VEGFR kinase inhibition. Further, only compound (21) was found to inhibit the kinase at IC50 of 0.5 µM, while compound (20) did not show any noteworthy inhibitory activity at tested concentrations [73].
8
R2
N N
O
Active compound 15a; R2; 4-F IC50; 0.06 µM
R1
N
O
Br
N N
S (15) Compd.
R1
15a; 15b; 15c; 15d; 15e; 15f;
3,4-diCH3 3,4-diCH3 3,4-diCH3 3,4-diCH3 3,4-diCH3 3,4-diCH3
R3 R2
N Br
S
Active compound 15a; R3; 4-Cl
(16)
R3
4-F 4-Cl 4-Br 4-CH3 4-OCH3 4-OH
4-Cl 4-Cl 4-Cl 4-Cl 4-Cl 4-Cl
O N
NH
N
N
Cl N N
S (17)
H3C O
O O
N
HO
S
N NH
O
N S
N
N
N H
N
Br
(19)
(18) O
O
O
(20)
N
O S HN
S
HN
HN
S
HN
O
O
O
N O
(21)
Figure 4: Thiazole derivatives as EGFR/VGFER kinase inhibitors (15-21). 2.1.2
Akt (PKB) protein kinases inhibitors Akt (PKB) protein kinases have been appeared as critical mediator of human physiology that controls an impressive array of diverse cellular functions, including the modulation of growth, survival, proliferation and metabolism. The isoforms of Akt (PKB) protein kinases play important role in the regulation of metabolism and cancers [74,75]. In this context, Chang et al. identified a new series of 2-substituted thiazole carboxamide derivatives as effective pan inhibitors against the isoforms of Akt (Akt1, Akt2 and Akt3) and as cell growth inhibitors against LnCaP, PC3, Du145 cell lines. Among the test compounds, one compound (22) (pyrrolopyridine core) which was found as most potent, inhibited the kinase activities of Akt1, Akt2 and Akt3 with IC50 values of 25, 196 and 24 nM, respectively. Furthermore, the compound was observed as potent inhibitor of phosphorylation of
9
downstream MDM2 and GSK3b proteins, and exhibited strong antiproliferative activity in prostate cancer cells [76]. In another study, Altintop et al. synthesized a new series of thiazole-containing compounds via targeting Akt pathway in cancer cells.
Additionally, cytotoxic studies were also
performed against on human lung adenocarcinoma (A549), rat glioma (C6), and mouse embryonic fibroblast cell lines (NIH/3T3). The in vitro cytotoxic screening revealed that compound (23) was most potent due to its significant inhibitory effects on A549 and C6 cell lines with IC50 values of 12 ± 1.73 µg/ml and 3.83 ± 0.76 µg/ml, respectively as compared to cisplatin (IC50;17.33 ± 2.08, 12.67 ± 3.06 µg/ml). Furthermore, compound (23) exhibited early apoptotic effect with 2.3 %, 4.6% and late apoptotic effect 36.5 %, 28.2 % on A549 and C6 cell lines, respectively. Compound (23) was also found as most potent Akt inhibitor in C6 cell line (71.66 ± 4.09 %), while cisplatin with 77.25 ± 5.75 % inhibition [77].
NH2
HN N
Cl
O S
N H
N
O
S NC
Cl
N
N H
(22)
N
CN
(23)
Figure 5: Thiazole derivatives as Akt (PKB) protein kinases inhibitors (22-23).
2.1.3
ALK/ TGF-β type I receptor kinase inhibitors The TGF-β type I receptor kinase (ALK5) is an attractive target in human tumours as well as in preclinical models of cancer. A number of potent, selective ALK5 inhibitors have been discovered which interact with the ATP-binding site of ALK5 [78]. A series of 5-(pyridin-2-yl)thiazoles were evaluated by Kim et al. for their ALK5 inhibitory activity in cell-based luciferase reporter assays. Amongst them, compounds (24) and (25) showed more than 95% inhibition at 0.1 µM in luciferase reporter assays using HaCaT cells transiently transfected with p3TP-luc reporter construct and ARE-luciferase reporter construct. The results recommended that only selected compounds might be considered as new leads in the development of novel antitumour agents [79].
10
Amada et al. have identified novel 5-(1,3-benzothiazol-6-yl)-4-(4-methyl-1,3-thiazol-2-yl)1H-imidazole derivatives as TGF-β (activin-like kinase 5 or ALK5) inhibitors. Among the test compounds, one compound (26) was found as potent inhibitor of ALK5 and TGF-β at a cellular level with (IC50; 5.5 nM), (IC50; 36 nM), respectively through induction of Smad 2/3 phosphorylation. In addition, topical application of 3% lotion of the compound (26) in mouse skin significantly inhibited Smad 2 phosphorylation i.e. (90% inhibition compared with vehicle-treated animals) [80]. In another study, Amada et al. reported novel 4-thiazolylimidazole derivatives as TGF-β (activin-like kinase 5 or ALK5) inhibitors. One compound namely N-{[5-(1,3-benzothiazol6-yl)-4-(4-methyl-1,3-thiazol-2-yl)-1H-imidazol-2-yl]methyl}butanamide (27), was the most potent elective ALK5 inhibitor with IC50; 8.2 nM. The compound (27) was also found to possess good inhibitory activity against TGF-β-induced Smad2/3 phosphorylation at a cellular level with IC50; 32 nM [81]. N
O O O
N H3C
NH2
N H
S N
O
N
H3C
N
(24)
NH2
N H
S
(25) CH3 N
N HN
N
N OH N S H3C
CH3 (26)
NH
S
O H3C
S
S
N
H N
CH3
N O (27)
Figure 6: Thiazole derivatives as ALK/ TGF-β type I receptor kinase inhibitors (24-27). 2.1.4
Aromatase inhibitors Several synthetic aromatase inhibitors (AIs) have been developed with slightly improved survival outcomes when compared to tamoxifen for the treatment of postmenopausal estrogen receptor-positive breast cancer. Aromatase is a heme-containing enzyme that exhibits its 11
inhibitory effect by blocking the last step in biosynthesis, the conversion of androgens to estrogens. Currently, type-I (steroidal drugs) and type-II (nonsteroidal drugs) are in clinical use [82,83]. Herein, thiazole-containing compounds have been reported as novel aromatase inhibitors. Mayhoub et al. presented a novel 2,4-diaryl-1,3-thiazole scaffold and provided more flexible synthetic pathways to build novel aromatase inhibitors with IC50 values in the nanomolar range. Using the new scaffold and optimizing the position of the hydrogen-bond acceptor on the ‘A’ ring of the lead molecule afforded compound 4-(4-(pyridin-3-yl)thiazol-2-yl)pyridine (28b), which had an aromatase IC50 value of 4 nM. In addition to the potent aromatase inhibitory activity of compound (28b), moderate NF-ҡB inhibitory activity was also observed. The methoxy derivative (28a) provided complete aromatase inhibitory selectivity with potency in the low nanomolar range (IC50; 23 nM). It was concluded that aromatase inhibitory activity was enhanced over 6000-fold by using a 1,3-thiazole as the central ring and modifying the substituents on the ‘A’ ring to target the Met374 residue of aromatase [84]. S Active Compound 28b IC50; 4nM
YX
A
N
B N
Compd. 28a; 28b;
X OCH3 -
Y C N
(28)
Figure 7: Thiazole derivatives as aromatase inhibitors (28).
2.1.5
HAT/HDAC (histone acetyltransferase/ histone deacetyltransferase) inhibitors Histone acetylase/histone deacetylase (HAT/HDAC) inhibitors are the exciting new class of drugs that play important roles in transcriptional regulation and pathogenesis of cancer. Protein lysine acetylation has been known as post-translational addition of an acetyl moiety to the ɛ-amino group of a lysine residue while, the reversible modification is known as Nɛacetylation. The enzymes HAT/HDAC involves in catalysis of acetylation and deacetylation of specific lysine residues in the histone tails and contributes in gene transcription since acetylation is associated with an open chromatin configuration and a permissive gene transcription state. Considerable attention has been focussed in these post-translational changes and their implications for the genesis of cancer. Recently, thiazoles have been identified as novel inhibitors of histone acetylase/histone deacetylase (HAT/HDAC) enzymes in the treatment of cancer [85]. 12
Secci et al. have identified a novel HAT (histone acetyltransferase) inhibitor namely 1-(4-(4chlorophenyl)thiazol-2-yl)-2-(alkyl-2-ylidene)hydrazine (29a-29c). The compounds showed selectivity for histone H3 acetylation and significant inhibition in first in vitro screening which was done against recombinant HAT Gcn5 and p300 at increasing concentrations (0.05, 0.1 and 0.2 µM). Afterward, compound (29a) was assayed for HAT inhibitor activity on human cells, HeLa (as control), neuroblastoma from neuronal tissue and glioblastoma from brain tumour. The structure analysis revealed that the 4-chlorophenyl moiety in the C-4 position of the thiazole nucleus showed better inhibition. Further, the cyclopentane ring modification and/or the aromatization/complication decrease the potency. On the other hand, ring opening and chain shortening showed better biological activity which might be due to limited steric hindrance in this portion of the lead compound (29a) [45]. A new series of structurally novel hydroxamic acid-based histone deacetylase (HDAC) inhibitors having both enzymatic and antiproliferative activity have been synthesized by Anandan et al. The thiazole ring attached to a piperazine spacer, which was capped with a sulfonamide group, was developed. The results revealed that hydroxamic acid derivatives (30a) and (30b) with IC50 values (0.09 and 0.07 nM) potently inhibited HDAC enzymes with the best activity as compared to positive control SAHA (IC50; 0.06 & 0.4 µM), respectively. From SAR viewpoint, it has been found that substituent with electron withdrawing groups adjacent to C=O plays an important role in enhanced activity of compounds (30a) and (30b). Rest of all the test compounds were found less potent [86]. In search of potent HAT inhibitors, Carradori et al. explored several new (thiazol-2yl)hydrazones including some related thiazolidines and pyrimidin-4(3H)-ones against human p300 and pCAF-HAT enzymes. The percentages of p300 inhibitory activities for all the compounds were tested at 100 µM while CPTH6 was used as standard drug. Two compounds (31) and (32), showed the highest p300 inhibition (>60%) than the standard drugs. From SAR viewpoint, the insertion of a thiazol-2-yl or pyrid-2-yl ring at the hydrazone function imparts strong HAT inhibition. On the other hand, among the bicyclic rings, the heteroaromatic (1H)indol-3-yl and 2(2H)-chromenon-3-yl furnished the most potent derivatives (31) and (32) with remarkable apoptosis and cytodifferentiation (formation of specialized cells such as muscle, blood, nerve cells from undifferentiated precursor) [87]. Oanh et al. arranged two series of benzothiazole-containing analogues as histone deacetylase inhibitors for cancer treatment. The compounds were also screened for their cytotoxicity 13
against five cancer cell lines, including SW620, MCF-7, PC3, AsPC-1, and NCIH460. Four compounds (33a-33d) bearing –OCH3 and NO2 groups displayed superior HDAC inhibition at 1 µg/ml, and were the most potent cytotoxic agents with the average IC50 values ranging from 0.81-5.49 µg/ml. It was found that compounds with 6C-spacer between benzothiazole and hydroxamic moieties had stronger HDAC inhibition and were more cytotoxic than the compounds with only 4C-spacer [88]. O O S
Cl Active compound 29a; R1; R2; CH3 Inhibitory Conc.; 0.2 mM Compd. 29a; 29b; 29c; O O
R1
HN N
2
R R1
N R
S
N N
S N
(29)
O NHOH
(30)
R2
Active compound 30a; R; 4-CH3 IC50; 0.09 nM
CH3 CH3 CH3 CH2CH3 CH2CH3 CH2CH3
Compd.
R 4-CH3 3,4-diOCH3
30a; 30b;
CH3 Cl
N HN
N
Active compounds 33c; OCH3 33d; NO2 Inhibitory Conc.; 1µ µg/ml
Cl
S
S N NH N NH
(32)
(31) Compd.
R
33a; 33b; 33c; 33d;
H CH3 OCH3 NO2
H
R N S
O HN
N H (33)
OH
O
Figure 8: Thiazole derivatives as HAT/HDAC inhibitors (29-33). 2.1.6
B-RAF inhibitors Many reports inferred that the B-RAF serine/threonine kinase alterations have been observed in different types of human tumours related to cell growth, survival and differentiation. BRAF gene (V600E) is most common in human cancer due to substitution of a valine for glutamic acid at position 600. Inhibition of B-RAF becomes important in many current human cancer therapeutic approaches. Therefore, Zhao et al. prepared a series of 4,5dihydropyrazole derivatives containing thiazole and thiophene moiety and evaluated as potential inhibitors of V600E mutant B-RAF kinase (B-RAFV600E) enzymes contributing to 14
tumour initiation and maintenance. According to the biological activity data, majority of the compounds showed effective B-RAFV600E inhibitory activity and antiproliferative activity against WM266.4 and MCF-7 cell lines. Compound (34) exhibited the most potent antiproliferative activity (IC50; 0.12 µM) against cell line WM266.4 and 0.16 µM against MCF-7 in comparison to sorafenib. Results showed that compound (34) was bearing the potent bioactivity with (IC50; 0.05 µM) against V600E mutant B-RAF kinase (B-RAFV600E). Furthermore, compound (34) induced remarkable apoptosis of MCF-7 and WM266.4 cells in a dose dependent manner. The results of this study might be helpful with in the search of promising B-RAFV600E inhibitor with potent activity [89]. In an another study, a new series of imidazo[2,1-b]thiazole-containing compounds were inspected by Abdel-Maksoud et al. for their in vitro antiproliferative activities against a panel of 57 human cancer cell lines at NCI. Some compounds exhibited comparable mean % inhibition values at 10 µM to sorafenib. Among ethylene analogs, compound (35) holding para-hydroxyphenyl terminal ring showed superior activity with lowest IC50 value 0.475 µM concentration against MCF-7 than sorafenib (IC50; 2.51 µM). The compound (35) was also equipotent to sorafenib over V600E-B-RAF (IC50; 39 nM), wild-type B-RAF, CRAF (IC50; 19 nM), MEK, and ERK kinases. SAR study revealed that hydrogen bond-forming group, such as the hydroxyl group of compound (35), attributed the potent kinase activity [90]. F
Cl F3C N
NH
N
HN O S O
N
S
N N
S HO (34)
N
N
S
(35)
Figure 9: Thiazole derivatives as B-RAF inhibitors (34-35). 2.1.7
Src and Abl kinase inhibitors c-Src and Bcr-Abl are two cytoplasmatic tyrosine kinases (TKs) associated with the development of tumour. The c-Src proto-oncogene plays a major role in the growth, progression, and metastasis of a plathora of human cancers. Through multiple oncogenic pathways, Src kinase modulates signal transduction in EGFR, Her2/neu, PDGFR, FGFR, and 15
VEGFR. Thus, blocking signalling through the inhibition of the kinase activity of Src will be an effective target for treatment of various types of cancers. Because of the structural homology between Src and Abl, several compounds originally synthesized as Src inhibitors have also been shown to be Abl inhibitors [91]. In an attempt, three novel series of 4-benzothiazole amino quinazolines of dasatinib derivative were described by Cai et al. and screened for their in vitro cytotoxic activity against six human cancer cell lines. These compounds were also screened for their Src and Abl kinase inhibitory activity. Cytotoxicity data indicated that 2, 4, 6-trimethylaniline series (38) with IC50; 3.5-24.5 µmol/ml, revealed noteworthy inhibitory activities against all the cell lines. Among the test compounds, compounds (36), (37) and (38) were found as dual inhibitors against Src/Abl kinase activity with more than 90 % inhibition. Thus, the disclosed structures might be the promising lead compounds to be developed as an substitute for current dasatinib therapy or for Imatinib-resistant patients [92]. Lombardo et al. investigated a series of substituted 2-(aminopyridyl)- and 2-(aminopyrimidinyl)thiazole-5-carboxamides as potential Src/Abl kinase inhibitors with promising antiproliferative activity against hematological and solid tumour cell lines. Out of the screend derivatives, derivative (39) (BMS-354825) was confirmed to be a highly potent, ATP competitive inhibitor of both Src and Bcr-Abl (IC50; <1 nM), with kinase inhibitory values of 16 ± 1.0 pM and 30 ± 22 pM, respectively. Further, compound (39) demonstrated 100-fold significant activity against c-kit and PDGFRβ and was orally active in a K562 xenograft model of chronic myelogenous leukemia at multiple dose levels demonstrating regressions of tumour [93].
16
NH2
NH2
O
O
O S CH3
N
CH3
CH3
O
S CH3
N
N
N
Cl
(36)
O
N
H3C O
S
Cl N
O N
NH CH3
N (37)
NH
O CH3
N
N N
H3C
N
H3C
N
N Cl
CH3
O
N N HO
(38)
N
N
HN
N N H
S
O
(39)
Figure 10: Thiazole derivatives as Src and Abl kinase inhibitors (36-39). 2.1.8
Tubulin polymerization inhibitors Microtubules are known to play a vital role in eukaryotic cell growth, division, motility and intracellular trafficking [94]. The natural functions of microtubules are regulated by their polymerization that occurs by a nucleation-elongation mechanism. In the development of the mitotic agents in the treatment of cancer, microtubules have been identified as the best cancer target. Also, the drugs of this class will continue to be important chemotherapeutic agents in the future as more selective approaches are developed [95,96]. Along with this, we have focused on the successful cancer chemotherapy from thiazole-containing compounds and their usefulness as tubulin polymerase inhibitors. Kryshchyshyn et al. developed some fused thiopyrano[2,3-d]thiazoles and screened them as anticancer agents against 60 tumour cell lines. Anticancer activity evaluation was done via three dose response parameter e.g. growth inhibition of 50% (logGI50) total growth inhibition (logTGI) Lethal concentration (logLC50) with in a concentration range (10-4 to 10-8). Out of test compounds, compound (40) (trifluromethane on phenyl ring) was most potent as cytostatic showing moderate selectivity ratio 3.25 at GI50 values 0.37 and 0.67 µM against leukemia, non-small cell lung cancer, colon cancer, CNS cancer, melanoma, prostate cancer and breast cancer subpanel with logGI50; −6.22, logTGI; −4.82, logLC50; −4.21. Compared analysis of the test compounds suggested that the high sensitivity of compound (40) have 17
some correlation with rhizoxin inhibition of β-tubulin in eukaryotic cells disrupting microtubule formation [97]. A series of cis-restricted combretastatins along with 5-membered heterocycles such as thiazole, pyrazole and triazole have been developed by Ohsumi et al. These analogues were tested for their antitubulin activity, cytotoxic activity against the colon 26 adenocarcinoma cancer cell lines and for antitumour activity colon 26 murine tumour models were used. Some of the tested heterocyclic analogues possessed significant antitubulin and cytotoxic activities. Among the tested thiazole-containing compounds, compound (41) demonstrated in vitro antitubulin activity (IC50; 1 µM), cytotoxicity (IC50; 57.5 nM). Further, compound (41) showed potent antitumour activity with tumour suppression (IR=75%, 40 mg/kg) comparable to that of AC-7739 [98]. Romagnoli et al. have introduced novel 2-substituted-4-(3ʹ,4ʹ,5ʹ-trimethoxyphenyl)-5-aryl thiazole-containing compounds in order to screen for their in vitro anticancer activity against various cell lines viz. HeLa, A549, HL-60, Jurkat, MCF-7 and HT-29. Biological findings revealed that antiproliferative activity is attributed to C-2 position of the thiazole ring. Among the test compounds, the thiazole derivative (42) exhibited most potent antiproliferative activity (GI50 1.7-38 µM) than the standard CA-4 against the tested cancer cell lines. Further compound (42) was found as most active inhibitor of tubulin polymerization (IC50; 0.89 µM) and strongly inhibited the binding of [3H] colchicine to tubulin (83% inhibition) [99]. Synthesis of two novel series of 3,4-diarylthiazol-2(3H)-ones and three 3,4-diarylthiazol2(3H)-imines and assessment for their cytotoxicity against a panel of human cancer cell lines was executed by Liu et al. These compounds were screened against Bel-7402, HEPG2, SMMC-7721, human liver cancer; MCF-7, human breast cancer; SW-1990, human pancreatic cancer; HCT116, human colon cancer; CEM, human leukemia using combretastatin A4 (CA-4), a novel cis-stilbene tubulin-binding agent as standard. Compounds (43a) and (43b) exhibited good cytotoxicity against the non-solid human CEM cell line (IC50; 0.24, 0.12 µM) with respect to CA-4 (IC50; 0.002 µM). While, EC50; 3.89 µM and >250 µM, respectively, was reported against a panel of solid human cancer cell lines. Resultant data suggested that compounds with the B-ring possessing the 3,4,5-trimethoxy system and the A-ring with a 4-methoxy substitution were more potent than the isomeric forms [100]. 18
By applying structure-based drug design techniques various colchicine site binding tubulin inhibitors in which ring B was replaced with pharmacologically active benzothiazole nucleus were designed and synthesized by Rao et al. Antiproliferative activity of these analogues were carried out against human cancer cell lines viz., prostate (DU-145, cervix (HeLa), lung adenocarcinoma (A549), liver (HEPG2) and breast (MCF-7), using colchicine as reference compound. The biological results shown that the bioisosters of 1,2,3-triazoles and 1,2,3,4tetrazoles were most active among all with IC50; 0.048-14.67 µM. Compounds (44) and (45) with a C-3 methyl substitution & C-6 methoxy, fluoro 2-phenylbenzothiazole moiety displayed favourable activity with IC50 value of 0.054 and 0.048 µM against the lung cancer cell line [101]. Antiproliferative activity of N,4-diaryl-1,3-thiazole-2-amines as tubulin inhibitors against (gastric adenocarcinoma SGC-7901 cells, lung adenocarcinoma A549 cells and fibrosarcoma HT-1080 cells was done by Sun et al. Most of the screened compounds exhibited moderate antiproliferative activity in comparison to CA-4 , nocodazole and SMART standard drugs. Out of the test compounds, one compound namely N-(2,4-dimethoxyphenyl)-4-(4methoxyphenyl)-1,3-thiazol-2-amine (46) exhibited the most potent antiproliferative activity, with IC50 values between 0.36 and 0.86 µM in the three cancer cell lines. Compound (46) also inhibited tubulin polymerization potently and disrupted microtubule dynamics in a manner similar to CA-4. Moreover, compound (46) effectively induced SGC-7901 cell cycle arrest at the G2/M phase in both concentration and time-dependent manners [102]. Shaik et al. introduced a series of 2-anilinopyridinyl-benzothiazole schiff bases and evaluated for their anticancer activity as well as cytotoxic activity. Among the test compounds, compound (47) was the most potent antiproliferating agent against A-549, MCF-7 and DU145 cell lines with GI50 values of 17, 12 and 3.8 µM, respectively. However, compound (48) has been emerged as most effective compound from the series by exhibiting a GI50 of 4.3 µM against A549 cell line. Compound (49) with trimethoxy groups on both the moieties was found to be better than E7010 in binding to the colchicine domain of tubulin, in silico. The test compound, (47) showed 37.85 and 66.09% of cell accumulation in G2/M phase at 2.5 and 5 µM concentrations,whereas the reference compound E7010 showed 50.21% cell accumulation in G2/M phase at 5 µM concentration. Thus, compound (47) competes with colchicine in binding to tubulin and causes cell cycle arrest in G2/M phase by inhibiting tubulin polymerization [103].
19
In an another study, Shaik et al. developed a series of imidazo[2,1-b]thiazole linked triazole conjugates and reported their antiproliferative activity against human cancer cell lines namely HeLa (cervical), DU-145 (prostate), A549 (lung), MCF-7 (breast) and HEPG2 (liver). Out of the tested conjugates, conjugates (50) and (51) demonstrated a significant antiproliferative effect against A549 (IC50 values of 0.924 and 0.778 µM) and MCF-7 (IC50 values of 1.737 and 1.013 µM) cell lines, respectively. SAR study revealed that electron-donating substituents like methoxy on the aryl ring enhanced the activity, while electronegative substituents like fluorine and chlorine on this ring suppressed the activity. Furthermore, compounds (50 and 51) significantly induced inhibition of tubulin polymerization and inhibition of binding of colchicines to tubulin by 70.2 and 74.3% (IC50 values of 1.62 and 1.43 µM), respectively as compared to nocodazole (71.0% inhibition, IC50; 1.59 µM) [42]. Combretastatin A-4 (CA-4) analogs of 3-(trimethoxyphenyl)-2(3H)-thiazole thiones were introduced by Banimustafa et al. and reported their cytotoxic activity against three human cancer cell lines namely MCF-7, MDA-MB-231 and T47D. Among the tested analogues, analog (52) with a substitution of 4-methyl showed potent activity against all cell lines with IC50 values 11.8-19.7 µg/mL. Moreover, bioassays results revealed that compound (52) depolymerized tubulin, inhibited cell proliferation, and induced apoptosis in cancer cells. In addition, compound (52) (selectivity index >5) has shown no significant toxicity towards non-tumoural cell line MRC-5 [104]. Synthesis and anticancer activity of 1,2,3-triazolo linked benzo[d]imidazo[2,1-b]thiazolecontaining compounds as tubulin polymerization inhibitors was executed by Shaik et al. Among the tested derivatives, derivatives (53a) and (53b) having halogen substituted on phenyl ring revealed significant cytotoxic activity against the human breast cancer cell line (MCF-7) with IC50 values of 0.60 and 0.78 µM, respectively. The flow cytometric analysis revealed that these conjugates cause cell cycle arrest at G2/M phase. Moreover, molecular docking study disclosed that compounds (53a) and (53b) could interact with the colchicine binding site between α and β subunits of tubulin [105]. Antiproliferative activity of cis-restricted 2-alkylthio-4-(2,3,4-trimethoxyphenyl)-5-arylthiazole analogues of combretastatin A-4 against human cancer cell lines HT-29, MCF-7, AGS, and a normal mouse fibroblastic cell line NIH-3T3 was done by Salehi et al. Compounds (54a) and (54b), containing the 2-(benzylthio) group on thiazole rings, were the most potent (IC50; <20 µM) in all three cancer cell lines. While replacement of 2-(benzylthio) 20
group decreases the activity of the compounds. However one compound (54a) with para chloro substituted on the phenyl ring and the 2-(benzylthio) group had the highest cytotoxic activity against the HT-29 cell line (IC50; 8.9 µM). In addition, some compounds were found to decrease the polymerization activity of the microtubule relative to the control CA-4 at 10 µM. The order of inhibition of tubulin polymerization was CA-4 > 54a > 54b. The compound with the 2-(benzylthio) group on the thiazole ring and the para chloro substituted 5-phenyl ring (54a) was the most potent inhibitor of tubulin polymerization [106]. Guggilapu et al. reported thiazole linked indolyl-3-glyoxylamide derivatives as novel tubulin polymerization inhibitors. All synthesized compounds were also screened for their in vitro cytotoxic activity against DU145 (prostate), PC-3 (prostate), A549 (lung) and HCT-15 (colon) cancer cell lines. Out of the test compounds, compound (55) displayed cytotoxicity of IC50; 93 nM against DU145 cancer cell line. Compound (55) showed anti-tubulin activity with an inhibition percentage of 68.5% in comparison to the podophyllotoxin (78.0%) The results from molecular modelling studies revealed that compound (55) bind at the colchicine binding site of the tubulin and exhibiting a cell cycle arrest at the G2/M phase [107]. Antiproliferative activity of new imidazo[2,1-b]thiazole-benzimidazole derivatives against HeLa (cervical), A549 (lung), MCF-7 (breast) and DU-145 (prostate) along with normal HEK-293 cell line was done by Baig et al. Among synthesized compounds, compound (56) demonstrated significant cytotoxicity against A549 lung cancer cell line (IC50; 1.08 µM) as compared to standard drug nocodazole (IC50; 1.807 µM). The tubulin polymerization assay revealed that compound (56) disrupted microtubule dynamics and induced abnormal spindle structure and centrosome which causes cell cycle arrest at G2/M phase. Furthermore, mitochondrial membrane potential and annexin V-FITC assay suggested that this compound induced cell death by apoptosis in (A549) human lung cancer cells. Docking studies also support the binding modes of compound (56) at the colchicine site of the tubulin to be act as antitubulin agent [108]. Wang et al. synthesized a series of 4,5-diarylthiazole-containing compounds in order to explore their potential as antiproliferative agents as well as microtubules stabilizing ability. Compound (57) with 3,4,5-trimethoxyphenyl group at the C-4 position and 4-ethoxyphenyl group at the C-5 position of 2-amino substituted thiazole was of the most potent with IC50 values of 8.4–26.4 nM against colon (HCT116 cell), liver (SMMC-7221), ovarian (A2780), hepatocellular (HEPG2), and ovarian (SK-OV-3) cancer cell lines, than CA-4 (IC50; 8.3-10 21
nM). Moreover, compound (57) has also been identified as potent tubulin polymerization inhibitor (resistance ratio 0.51-2.24). Tubulin polymerization assay and an EBI competition binding mechanism revealed that (57) could block the progression of cell cycle in the G2/M phase and result in cellular apoptosis in cancer cells similar to colchicines [109].
2.1.9
Topoisomerase inhibitors DNA topoisomerases are ubiquitous enzymes that are required for proper chromosome structure and segregation and play important roles in the topological states of DNA, such as DNA replication, transcription, and recombination. DNA topoisomerases are categorized into four subfamilies IA, IB, IIA and IIB, and each family possess unique mechanistic features [110,111]. These enzymes are also known for maintenance of genome stability by catalyzing the passage of individual DNA strands (topoisomerase I) or double helices (topoisomerase II) through one another. Clinically used drugs like camptothecin targets topoisomerase I (topo I), while doxorubicin and etoposide are typical topoisomerase II (topo II) inhibitors. Hence, topoisomerases are suitable targets for important anticancer drugs. Herein, thiazole derivatives exhibiting promising topoisomerase inhibitory activity are being addressed in this section. In this context, Choi et al. reported solid phase combinatorial synthesis of biologically active benzothiazole-containing compounds and assessed them for topoisomerase II inhibitory activity. Generally, all the screened derivatives demonstrated good inhibition of topoisomerase II enzyme at 100 µM. One compound 2-(3-amino-4-methylphenyl) benzothiazole (58) displayed potent topoisomerase II inhibitory activity at IC50; 71.7 µM, comparable to etoposide (IC50; 78.4 µM) [112].
22
H
S
O
H2N
H N
N
S
N
O
H S
O F
F F
(40)
NH2
O H3C H3C O
O
H3C H3C
A O
O CH3
S
O
H3C
O
N
A
B O
O O
Compd.
R
43a; 43b;
H Cl
AC-7739
O O O
CH3 CH3
CH3
N
(42)
H3C
O
S
N N N
O
N O
S (45)
F
CH3
H3C
N
O S
O O CH CH3 3
N
N N
S
OCH3 N
NH
S N
N
N NH
O O (51)
N
N N
N N
(50)
S
N
OH CH3 O
O
OCH3
O
H3C
H N
OCH3
Cl
OCH3
N
NH
H3CO
OCH3
F
OCH3
(49) (48)
S
OCH3
N N
S
OCH3
(47)
OCH3
OCH3
N
NH
O CH3
(46)
OCH3 N
N
NH
CH3
O O CH CH3 3
(44) H3C O
CH3
N N N
CH3
O
(43)
CH3
N
S
CH3
CH3
NH2 O
NH
H2N
CH3
O H3C
(41) R
B
O
O CH 3 CH3 O
CH3 O
CH3 O CH3 O
S
N S
CH3 (52)
Figure 11: Thiazole derivatives as tubulin polymerase inhibitors (40-52).
23
O
R N
N
N H
N
S N
N
S
F
H3C
(53) Compd. 53a; 53b;
O
O O
R H CH3
Compd.
R
54a; 54b;
Cl F
CH3
CH3 (54)
NH2
H3C O
O
H3C H3C
O NH
F
N O
S N
(55)
F
H N
N
F N
HN O
S
N
R
CH3 (56)
N
S
O
N
O
H3C
O O
S (57)
CH3
Figure 11 (cont.): Thiazole derivatives as tubulin polymerase inhibitors (53-57). 2-Aminothiazolyl quinolones were synthesized and screened for their antimicrobial and anticancer potential by Cheng et al. To our interest, in vitro cytotoxicity of the synthesized compounds was carried out against L929 (normal mouse fibroblast) cells. The results revealed that compound (59) exhibited lowest toxicity against L929 cells at IC50 value of 289 µg/mL. Further, docking results showed that compound (59) was able to bind with topoisomerase IV-DNA through hydrogen bonds between molecule and residue Arg418 of topoisomerase IV as well as through π-π stacking between molecule and base DA16 of DNA [113]. Beauchard et al. produced a set of novel thiazoloindolo[3,2-c]quinoline, 8-substituted-1Hindolo[3,2-c]quinolone derivatives and evaluated for DNA interaction, topoisomerases inhibition and cytotoxicity against (human leukemia cells) HL60 and HL60/MX2. Most of the synthesized derivatives exhibited interesting in vitro cytotoxic activity against MCF-7 and MDA-MB-231 tumour cells at concentration of 10 µM. Compounds bearing imidazoline cationic side chain on the thiazole ring (60-62) exhibited stronger cytotoxicity. The linear aminothiazoloindolo[3,2-c]quinoline derivative which acts as a DNA-intercalating agent, also displays a significant anti-proliferative activity [114].
24
N
CH
NH2
F
N
N
CH3 S
S
F
(58)
O CH3
N N
NH2
S
N
(60)
(59)
N
N N N N
H N S
N N N
H N
S N N
N N
NH
N
N N (62)
(61)
Figure 12: Thiazole derivatives as topoisomerase IV inhibitors (58-62). 2.1.10 CDC7 inhibitors The Cell division cycle 7 (CDC7) protein kinase is essential for DNA replication and maintenance of genome stability. Given its essential function in cell proliferation, Cdc7 has been considered as a novel target for cancer therapy. Herein, Reichelt et al. have identified trisubstituted thiazoles as CDC7 kinase inhibitors in cancer treatment. These thiazole based compounds were closely related kinase that shares both structural and functional homology with CDC7 kinase. Compound (63) having ester on 5th position and hydroxyl on 4th position of the thiazole was the most promising hit in a series of thiazoles for CDC7 kinase activity with IC50 of 0.323 µM, and no activity at IC50; >125 µM against CDK2. Further amide (64) having 2,4-diCl substitution on phenyl ring was the most potent CDC7 inhibitor with an IC50; 0.00377±0.0016 µM [115].
Cl
Cl N
H2N
OH
N
N O
S
CH3
N
N
O (63)
NH2
S (64)
O
Figure 13: Thiazole derivatives as CDC7 inhibitors (63-64). 2.1.11 Monoacylglycerol lipase (MAGL) inhibitors 25
Human monoacylglycerol lipase (MAGL) is a serine hydrolase enzyme that belongs to the super family of α/β-hydrolases. It has been reported that MAGL regulates a fatty acid network in cancer and is highly aggravated in aggressive cancer cells, including melanoma, breast cancer, ovarian cancer, colorectal carcinoma, and prostate cancer. The cancer promoting activity is due to an elevated free fatty acids (FFA) level, which suggested a new metabolic function of this enzyme. Hence, Afzal et al. reported new N-[4-(1,3-benzothiazol2-yl)phenyl]acetamide derivatives as novel inhibitors of human MAGL enzyme. Compound (65a) was found to be most active with IC50 value of 6.5 nM. In addition to MAGL enzyme assay, in vitro anticancer activity was also performed against NCI-60 cancer cell lines. Overall, one dose assay results showed that majority of the compounds were active against MCF7 and MDA-MB-468 breast cancer cell lines. Out of the test compounds, compounds (65b) and (65c) showed potent anticancer activity at GI50 values for MCF-7 (32.5, 37.1 nM), against MDA-MB-468 (23.8, 25.1 nM), respectively as comparedto 5-FU [116].
R N
Compd. NH
S N H
O
65a; 65b; 65c;
R 3-Cl, 4-F 4-Cl 2,6-Cl2
(65)
Figure 14: Thiazole derivatives as monoacylglycerol lipase (MAGL) inhibitors (65). 2.1.12 Na+/K+-ATPase inhibitors Several types of cancers, especially glioblastomas, melanomas and NSCLCs are associated with dismal prognoses involve the inhibition of various types of ion channels, particularly the alpha-1 subunit of the Na+/K+-ATPase (NAK). These cancers are also resistant to conventional radiotherapy and chemotherapy. Impairing NAK alpha-1 activity represents an efficient approach to killing MDR cancer cells. In this context, Lefranc et al. assessed 26 thiazoles (including 4-halogeno-2,5-disubtituted-1,3-thiazoles) and 5-thienothiazoles for their in vitro anticancer activity against a panel of 6 human cancer cell lines, including glioma cell lines. Compounds (66a) and (66b) displayed ~10 times greater in vitro anti-NAK activity at 1 mM (bioselectivity indices > 5) than perillyl alcohol (POH). Further, compounds (66a) and (66b) displayed inhibitory activity > 50% at 1 mM on purified guinea pig brain NAK, whereas only compound (66b) displayed inhibitory activity > 50% at 1 mM on purified 26
guinea pig kidney NAK. The kinetic study results revealed that compound (66b) interacts by non-competitive inhibition with both Na+/K+ ions [117].
N N
R
S O
Compd.
R
66a; 66b;
Cl Br
(66)
Figure 15: Thiazole derivatives as Na+/K+-ATPase inhibitors (66). 2.1.13 Carbonic anhydrase inhibitors Carbonic anhydrases (CAs) are metalloenzymes which catalyze this reversible hydration reaction of carbon dioxide to bicarbonate and protons (CO2 + H2O
HCO3-+ H+). They
play an important role in tumourigenicity and many other physiological or pathological processes. Sixteen different CA isoforms are known, which vary in localization and tissue distribution, being cytosolic (I, II, III, VII, and XIII), membrane bound (IV, IX, XII, and XIV), mitochondrial (VA and VB) and secreted (VI) forms. The membrane bound CA IX and XII isoforms are known as the CAs associated with cancers, being expressed in a limited number of normal tissues. Solid tumours generally characterized by elevated acidic pH and low level of oxygen (hypoxia) and leads to overexpression of CA IX and CA XII. CA IX also plays a role in providing bicarbonate to be used as a substrate for cell growth, whilst it is established that bicarbonate is required in the synthesis of pyrimidine nucleotides. Motivated by the above findings, Ibrahim et al. reported synthesis and carbonic anhydrase inhibitory properties of benzothiazole-6-sulfonamides. Most of the novel compounds were highly potent inhibitors of the tumour-associated hCA IX and hCA XII with KIs in the nanomolar range 3.5 to 45.4 nM. Among the test compounds, compounds (67) & (68) were found as most potent inhibitors against the slow cytosolic isoform hCA I with KIs in the range of 2.6-12.0 nM. The rest of compounds were found to have moderate activities against hCA I [118]. Suthar et al. have designed novel 4-(4-oxo-2-arylthiazolidin-3-yl)benzenesulfonamide derivatives and checked for their in vitro anticancer as well as selective carbonic anhydrase IX (CA IX) inhibitory activity. The resultant data suggested that compound (69) was found to be the most potent and selective inhibitor of CA IX with inhibitory constant (KI) value of 2.2 nM (selectivity ratio 381 against CA I). In addition, compound (69) showed IC50 values of 5.03 µg/ml (cisplatin: 6.56 µg/ml), 5.81 µg/ml (cisplatin: 5.85 µg/ml), and 23.93 µg/ml (cisplatin: 2.75 µg/ml) against COLO-205, MDA-MB-231, and DU-145 cell lines, 27
respectively. Anticancer activity results showed that compound (69) caused cell shrinkage, nuclear condensation, and nuclear fragmentation events that are characteristic to apoptosis of COLO-205 cells [119]. O O H2N S O
N S
O N H
N
N N
O
O S H2N O
NH
N
Cl (69)
(67)
N
N
N
O
S
O O S H2N O
S
S HN
NH
S
NH2 O
N
S (68)
Figure 16: Thiazole derivatives as carbonic anhydrase inhibitors (67-69). 2.1.14 Sphingosine kinase inhibitors Sphingosine kinases (SphK1, SphK2) are regulators of sphingosine-1-phosphate (S1P) that play an essential role in membrane formation and act as modulators in cell signaling processes. Sph is phosphorylated by SphK to form S1P. SphK exists in two isoforms, SphK1 and SphK2, which differ in their substrate preferences, subcellular localizations and tissue distributions, suggesting that they perform different physiological roles. Sphingosine kinase (SphK) inhibitors are another therapeutic option for treatment of cancer and inflammatory diseases that can promote cell apoptosis and modulate autoimmune diseases. Thus, Vogt et al. have reported 2-aminothiazole-containing compounds as sphingosine kinase inhibitors. From this series, compound (70), ST-1803 exhibited 59.4 ± 3.3% inhibition of SphK1 and 50.0 ± 9.9% inhibition of SphK2 at 10 µM demonstrating the most potent sphingosine kinase inhibitor. An extensive screening of tri-thiazole compound, N-(4-methylthiazol-2-yl)-(2,4’bithiazol)-2’-amine (70), ST-1803 against both the isoenzymes demonstrated IC50 values of 7.3 µM (SphK1), 6.5 µM (SphK2) as a promising candidate for further in vivo studies [120]. H N
S N N
S N CH3
S (70)
28
Figure 17: Thiazole derivative as sphingosine kinase inhibitors (70). 2.1.15 IMP dehydrogenase inhibitors Nucleotide coenzymes have significant role in cellular metabolic processes such as nicotinamide adenine dinucleotide (NAD) in the case of dehydrogenases. Altered NAD metabolism has been observed in many cancers. These dinucleotides are potent inhibitors of inosine 5’-monophosphate dehydrogenase (IMPDH), a rate-limiting enzyme of de novo guanine nucleotides biosynthesis. Thus, thiazole-4-carboxamide adenine dinucleotide (TAD) analogues T-2’-MeAD and T-3’-MeAD containing, respectively, a methyl group at the ribose 2’-C-, and 3’-C-position of the adenosine moiety, were introduced by Franchetti et al. as potent selective human inosine monophosphate dehydrogenase (IMPDH) type II inhibitors. Biological evaluation of dinucleotide (71b) inhibitor of recombinant human IMPDH type I and type II resulted in a good inhibitory activity (0.52 & 0.66 µM, respectively). Inhibition of both isoenzymes by compound (71a) (T-2’-MeAD) and (71b) (T-3’-MeAD) was noncompetitive with respect to NAD substrate. Binding of T-3’-MeAD was comparable to the parent compound TAD, while T-2’-MeAD proved to be a mild inhibitor. On the other hand, no significant variation was found in inhibition of the IMPDH isoenzymes. Compounds (71a) and (71b) were found to inhibit the growth of K562 cells at IC50; 30.7 and 65.0 µM, respectively than tiazofurin (IC50; 4.5 µM) [121]. Active Compound 71b; Inhibitory Conc.; 0.52 & 0.66 µM
NH2 N N N
N
R
CONH2 S
R1
O O O P O P OH OH (71)
O
N Compd.
R
R1
71a; 71b;
CH3 H
H CH3
OH OH
Figure 18: Thiazole derivatives as IMP dehydrogenase inhibitors (71).
2.1.16 Pin1 inhibitor Pin1 (Protein interacting with NIMA1) is a peptidyl prolyl cis–trans isomerase (PPIase) which catalyse the isomerization of the amide bond of pSer/Thr-Pro in its target proteins and is a novel promising anticancer target. A number of structurally distinct small-molecule 29
inhibitors of Pin1 have been reported recently. In this context, Zhao et al. reported a series of new thiazole-containing compounds and assessed their inhibitory activities against human Pin1 using a protease-coupled enzyme assay. All the monosubstituted derivatives exhibited potent Pin1 inhibitory activity within IC50 range of 2.93-51.1 µM. Among them, compound (72) oxoacetic acid was the most potent with IC50; 2.93 µM. The results suggested that an oxalic acid and thiazole ring moiety might be suitable in developing potent Pin1 inhibitors in cancer treatment [122]. HO O
O NH HN
N O
S
O (72)
Figure 19: Thiazole derivatives as Pin1 inhibitor (72). 2.1.17 USP7 inhibitors Herpesvirus-associated Ubiquitin-Specific Protease (USP7, represents the oncogenic protein) interacts with Mdm2 and stabilizes it. USP7 has been identifies as a potential drug target for cancer therapy. USP7 inhibitors have been recently shown to suppress in vitro and in vivo tumour cell growth. In this context, Chen et al. have executed the synthesis and anticancer screening of a series of thiazole-containing compounds against cancer cell lines as well as USP7 enzyme inhibitors. Generally, the test compounds exhibited their effect by inducing cell death in a p53-dependent and p53-independent manner. Compounds (73a-73b) were found as most potent compounds with micromolar concentration given in the table 1. The molecular docking studies revealed that that P22077 (reference compound) and (73a) might bind to the ubiquitin binding pocket to competitively inhibit the binding of ubiquitin to USP7 [123]. Table 1 Thiazole-containing compounds (73a-73b) as USP7 inhibitors (IC50; µM); Compnd.
HCT116 (p53wt/wt)
RMPI-8226 (p53mt/mt)
H1299 (lack of p53 gene)
73a
8.45 ± 1.76
10.97 ± 0.73
6.21 ± 3.28
73b
6.36 ± 2.14
6.11 ± 0.51
3.68 ± 1.10
30
N
O2N
R Compd.
R
S S
Cl
73a;
-COCH3
Cl N
73b;
O
C
N H
F
(73)
Figure 20: Thiazole derivatives as USP7 inhibitors (73). 2.2
Thiazole-containing compounds endowed with anticancer activity: Other modes of action Several key signaling pathways-including PI3K/AKT/mTOR, RAS/MEK/ERK, and p53have been implicated in the tumourigenesis [124]. In the age of small molecule for targeted therapies, thiazole and their derivatives are the emerging class of anticancer which exhibited potential activity against various kinases as well as signalling pathways. In this review, we have also emphasized on some other modes of actions of thiazole-containing compounds besides their action as enzyme inhibitors. Some other modes of actions have been described as: mTOR inhibitors, antifibrotic agents, DNA intercalating agents, apoptotic/angiogenesis inhibitors, NF-kB inhibitors and RSK2 inhibitors.
2.2.1
Thiazole-containing compounds as antifibrotic agents Fibroblasts play a pivotal role in the normal wound healing or tissue repair process and are are associated with cancer cells and cancer progression. Fibroblasts are associated with an array of cytokines targeting the so-called cancer-associated fibroblast (promoters of tumour growth and progression) which is a novel and promising therapeutic strategy against cancer. In this context, a series of 2-amino(imino)-4-thiazolidinone derivatives and 4-Raminothiazol-2(5H)-ones was screened for its antifibrotic and anticancer activities by Kaminskyy et al. The antifibrotic activity results revealed that compounds which significantly reduced the viability of fibroblasts did not possess antiproliferative or antineoplastic effects at a concentration range of 0.01-100 µM. Only compound (Z)-5-(4-chlorobenzylidene)-2-(4hydroxyphenylamino)thiazol-4(5H)-one (76), which possessed significant anticancer activity, displayed moderate antifibrotic action. However, xCelligence system testing of compounds confirmed that compounds (74), (75), (77) and (78) demonstrated most potent antifibrotic activity similar to standard drug pirfenidone and did not scavenge superoxide radicals [125]. 31
O
O O N
H3C N
H3 C S
N
O
N H
NH
S
N N
S F
O
N
F
(74)
H N S
(75)
F
O
CH2 O N
O
N S
N
N O
S
S HO
NH
S S
Cl
NH
N
(76)
O (77)
Cl N H
(78)
Figure 21: Thiazole derivatives as antifibrotic agents (74-78). 2.2.2
NF-ҡB inhibitors NF-kB and AP-1 are important transcription factors and promising targets for the development of anti-cancer therapeutics associated to variety of genes namely IL-6, IL-8, MMP-9, COX-2, and MCP-1. Similarly, the translation initiation factors, eIF-4E, eIF-4F, and eIF-4G, as well as mTOR have been shown to play a significant role in tumour progression. The thiazole compounds have been found as inhibitors of NF-ҡB that may be useful in treating cancer. 2-Thiazol-5-yl-3H-quinazolin-4-one derivatives were scrutinized by Giri et al. in order to explore their potential as inhibitors of NF-ҡB, AP-1 mediated transcription and eIF-4E mediated translational activation which play a pivotal role in initiation and progression of cancer. Some of the test compounds produced a very good dose dependent inhibition of NFҡB and AP-1 mediated transcriptional activity. Compounds (79a), (79b) and (79e) strongly inhibited (>70%) TNFα induced NF-ҡB gene expression at the 3.3 µM concentration. Similarly compounds (79c) and (79d) were also found to have IC50 of 3.3 and 5.5 µM, respectively. Of these, only compound (79c) was found to be inhibiting cell growth at 3.3 µM by more than 20% against FaDu cell lines [126].
32
R2 N
N S
R1 NH
N O
Active compound 79c; R1; CH3, R2; CH3, R3; Cl Inhibitory Conc.; 3.3 µM
R3
Compd.
R1
79a; 79b; 79c; 79d; 79e;
4-ClC6H4 COOC2H5 CH3 C6H5 4-ClC6H4
R2
R3
C6H5 OCH3 CH3 Cl CH3 Cl CH3 Cl C6H5 Cl
(79)
Figure 22: Thiazole derivatives as NF-ҡB inhibitors (79). 2.2.3
PI3K/mTOR inhibitor Rapamycin is a clinically successful (mTOR) allosteric inhibitor, and its derivatives of rapamycin have been successfully developed for treatment of cancer. Recently, Xie et al. have produced rapamycin-benzothiazole hybrid derivatives for their anti-cancer activity against Caski, CNE-2, SGC-7901, PC-3, SK-NEP-1 and A-375 human cancer cell lines. Some of the tested derivatives were found as potent anticancer agents. Specifically compound (80) was most active displaying IC50 values of 8.3 (Caski) and 9.6 µM (SK-NEP-1), respectively. Moreover, it was found that compound (80) causes G1 phase arrest, induces apoptosis in the Caski cell line and significantly decreased the phosphorylation of S6 ribosomal protein. Compound (80) was able to inhibit the cancer cell growth by obstructing the mTOR pathway and might be suitable drug candidate to develop new mTOR inhibitor [127]. Ali et al. scrutinized in vitro anticancer activity of a novel series of imidazo[2,1-b]thiazoles bearing pyrazole derivatives against NCI-60 cell panel at a dose of 10 µM. The biological testing indicated that against the CNS SNB-75 and Renal UO-31 cancer cell lines, compounds (81-83) demonstrated most potent activity with a percentage cell growth of 59.16-110.76 %. These compounds (81), (82) and (83) also showed significant results for toxicities, druglikeness, and drug score profiles and have considerable correlations with rapamycin (mTOR inhibitor). In silico studies, revealed that compounds (81-83) could be considered as promising leads for further robust scientific exploration and development of more potent anticancer agents in future [128]. Xie et al. investigated 1-alkyl-3-(6-(2-methoxy-3-sulfonylaminopyridin-5-yl)benzo[d]thiazol2-yl)urea derivatives for their inhibitory activity against PI3Ks and mTORC1 as well as antiproliferative activities against HCT116, MCF-7, U87 MG and A549 cell lines. Compound (84) with a methoxy group at the 2nd-position of pyridine ring exhibited most potent 33
antiproliferative activity against all the cell lines (IC50; 0.30-0.45 µM). Further, cell based activity results revealed that compound (84) exhibited significant activities against PI3K and mTORC1. The inhibitory activities against PI3Kα, PI3Kβ and PI3Kγ were higher than the standard drug BEZ235. The results also strongly recommended that 1-alkyl-3-(2,3disubstituted pyridin-5-ylbenzo[d]thiazol-2-yl)urea can be used as PI3K and mTOR dual inhibitors [129]. Li et al. developed nineteen derivatives of 2-methoxy-3-phenylsulfonylaminobenzamide and 2-aminobenzothiazole fragments and reported their anticancer activity against HCT-116, A549, MCF-7 and U-87 MG cell lines. These compounds were also evaluated as PI3K/ AKT/mTOR inhibitors. Interestingly, compound (85) exhibited most potent anticancer activity with IC50; 0.50-4.75 µM against all the cell lines used when compared with the standard drug BEZ235. Western blot assay revealed that compound (85) significantly block the PI3K/AKT/mTOR pathway and decreases the tumour growth [130]. Hayakawa et al. aimed to synthesized imidazo[1,2-a]pyridine derivatives as potent PI3 kinase p110α inhibitors. Seqential optimization of compound 3-{1-[(4-fluorophenyl)sulfonyl]-1Hpyrazol-3-yl}-2-methylimidazo[1,2-a]pyridine afforded thiazole derivative (86) which exhibited antiproliferative activity (IC50; 0.21 µM) against A375 cells, suggesting that PI3K p110α is a potential target in cancer treatment (exhibiting 60-fold selectivity for p110α). In HeLa cells, furthermore, compound (86) suppressed tumour growth by 37% in HeLa xenograft mice when dosed intra-peritoneally at 25 mg/kg once daily for 2 weeks with no significant toxicity [131]. 4’, 5-Bisthiazole variant of an (S)-proline-amide aminothiazole-urea drivatives as selective phosphatidylinositol-3 kinase alpha inhibitors (PI3K inhibitors) were identified by Fairhurst et al. Among the screened derivatives, derivatives (87) and (88) were capable of inhibiting signaling through the PI3K pathway for greater than 8 hours demonstrated most potent and selective PI3Kα inhibitor within an IC50 values range of 0.009-0.29 µM. Thus, (S)-prolineamide aminothiazole-urea generated tricyclic series hold the significance to be used as selective PI3Kα inhibitor [132].
34
S H
Cl S N
OCH3
N
NC
CH3 H N S
(82)
CH3 F O S HN O O
O
N
N N CH 3
N
O
O
N
N
S
H3C
N
S
O O
CH3
N N
N
(81)
N
(80)
N
O
O
O N H3C
N
O
H3C
F
(83)
(84) S
H3C O
Cl
N H3C S
N N
N
O S
CH3
O
O
S
H3C
N H
S
N N
S
HN N
O
CF3 CH3 CH3
N
N
(86)
H2N
N S
HN
O NO2
(85)
NH
NH
CH3 O
H2N
N
BEZ235
N
O
HN N
O
N
CH3 H3C CH3
O (87)
H2N
(88)
Figure 23: Thiazole derivatives as PI3K/mTOR inhibitor (80-88). 2.2.4
Apoptotic/angiogenesis agents Dysregulation of the programmed cell death process (apoptosis) is a hallmark of many types of malignancies. Apoptosis comprises of intrinsic or extrinsic pathways in which caspase-3 plays a central role in both types of apoptotic pathways. Keeping this in mind a novel compound 2-chloro-N-(2-(2-(5-methylpyridin-2-ylamino)-2-oxoethylthio)-benzo[d]thiazol-6yl) acetamide (89) (YLT322) was synthesized by Xuejiao et al. as potent anti-tumour agent via inducing apoptosis both in vitro and in vivo against human cancer cells. After compound YLT322 (89) treatment, it was observed that apoptosis was associated with activation of caspases-3 and -9, but not caspase-8 due to concomitant increase in their cleavage, indicative of enzyme activation. Addition of the irreversible inhibitors, Z-VAD-FMK (caspase inhibitors) and Ac- LETD-FMK(caspase-9 inhibitors) significantly decreased the percentage of apoptotic cells after treatment with compound YLT322 (89), suggesting that cell apoptosis induced by YLT322 (89) may be dependent on caspase activation. Moreover, YLT322 (89) suppressed the growth of established tumours in xenograft models in mice without obvious side effects [133]. 35
Choi et al. examined a novel compound N-(5-(2-bromobenzyl) thiazole-2-yl) benzofuran-2carboxamide (90) for its cytotoxicity and anticancer effect on cell growth, apoptosis, and angiogenesis against human HCC cells (HEPG2, Hep3B, and Huh-7 cells). HCC cells were exposed to four concentrations from 0.1 to 20 µM of (90) for 48 h whereas sorafenib, a commercial drug was used as standard. These results showed that compound (90) not only inhibited cell growth and angiogenesis, but also induced apoptosis of human HCC cells in a dose-dependent manner [134]. In search of potential chemotherapeutics for cancer treatment Tantaka et al. herein reported a new series of novel 2-aryl-amino-4-(3′-indolyl)thiazoles. In vitro cytotoxicity study was done against a panel of human cancer cell lines namely lung (A549), cervix (HeLa), liver (HEPG2) and breast (MCF-7 and MDA-MB-231) at micromolar IC50 range. Out of the test compounds, compound (91) was acknowledged as the most potent cytotoxic agent against MCF-7 breast cancer cells with an IC50 value of 1.86 µM and low toxicity on normal human cells as compared to doxorubicin. Flow cytometry mechanism showed that (91) induced ROSmediated (Reactive Oxygen Species) apoptosis in MCF-7 cells through the mitochondrial apoptosis pathway [135]. The anticancer activity of new series of spirooxindole-pyrrolothiazole-containing compounds were studied by Lotfy et al. All the newly synthesized compounds were scrutinized for their in vitro activity against breast cancer cell line MCF-7 and K562-leukemia. Compound (92) was found to be the most potent against MCF-7 breast cancer cells and K562-leukemia, with IC50 values of 15.32 ± 0.02 and 14.74 ± 0.7 µM, respectively as compared to 5-FU. Annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) (AV/PI) dual staining assay revealed that compound (92) increased the apoptosis percentage two fold at concentration of 10 µM [136]. Kumar et al. developed a multicomponent synthesis of molecular hybrid of pyrazole and thiazole in order to find out their in vitro apoptosis inducer activity on granulosa cells of ovarian antral follicles of goat (Capra hircus). Among the test compounds, only compound (93) exhibited maximum DNA damage or potency to induce apoptosis with percentage of apoptosis 25.61 ± 2.95 in comparison with control (5.14 ± 0.44). Hence, it can be concluded that substituted phenyl ring attached to the thiazole and pyrazole scaffolds contributed as apoptosis inducer activity in terms of electronic and steric parameters [137].
36
The pro-apoptotic and anti-angiogenic effect of newly synthesized thiazole, pyridine, pyrazole, thiazolopyridine and pyrazolopyridine progesterone derivatives was studied by Yahya et al. These compounds were evaluated for their cytotoxic effect against human breast cancer cells (MCF-7) using tamoxifen as standard drug. Among the synthesized thiazolecontaining compounds, derivatives (94a) and (94b) showed anticancer activity (IC50; 5.28 & 5.87 µM) against MCF-7 cancer cell line as compared to tamoxifen (IC50; 3.53 µM). From SAR viewpoint, introduction of a methyl group to the steroid moiety in compound (94a) contributed more potent compound than a phenyl group in compound (94b). It has been found that these compounds displayed significant pro-apoptotic effect through the down regulation of BCl-2, survivin, and CCND1 genes [138]. A series of pyridinyl-thiazolyl carboxamide derivatives was identified by Zhou et al. in order to examined angiogenesis in human umbilical vein endothelial cells (HUVECs) by in vitro method. The biological data revealed that compound (95) found to inhibit angiogenesis by suppressing key angiogenesis signaling pathways, such as ERK, JNK and FAK-Src etc. In addition, compound (95) also showed excellent effect on a breast tumour growth model with the dosage of 30 mg/kg [139].
37
S O
S
H3C
S
NH
O
O
(89) YLT322
(90)
S
HO N N
HN S
H
N
N H
H
(91)
H3C O
Br
N HN
O
N
N
Cl
H N
Br
O (92)
N
H N
Cl
N S
N N
Br
Compd.
R
94a; 94b;
-C6H5 -CH3
(93)
H3C
S
N N
H H O
H
(94)
N N O CH3
N H
N
CH3 HN S
H3C N
O (95)
Figure 24: Thiazole derivatives as apoptotic/angiogenesis agents (89-95). 2.2.5
RSK2 inhibitors RSK2 has been identified as a potential oncology drug development target based on its role in MAP kinase signalling and more recently on its importance for the RAS-ERK pathway as it effects tumour cell invasion. In this context, Andreani et al. carried out synthesis of a new series of imidazo[2,1-b]thiazole guanylhydrazones and screened them as RSK2 inhibitors and tumour growth inhibitors. Analogues with F substitution (96a) and with Br substitution (96b) depicted most potent tumour cell growth inhibitors with mean pGI50 6.25, 6.51 respectively either due to transport across cell membranes or might be critical nature of RSK2. Further to study the effect of RSK2 kinase on tumour cell growth, a cell-based assay was performed on 38
human breast cancer line MCF-7 and normal human breast line, MCF-10A. Of these, compounds (96a) and (96b) have the lowest IC50 selectively against MCF-7, MCF-10A and the biomarker GSK3 evidenced that compounds significantly affected the RSK2 target in cells [140]. NH2 HN N N
R S
NH
NO2 N
Compd.
R
96a; 96b;
F Br
(96)
Figure 25: Thiazole derivatives as RSK2 inhibitors (96). 2.2.6
DNA intercalating agents DNA-intercalating ligands as anti-cancer drugs have developed greatly since the clinical success of doxorubicin (adriamycin) and daunorubicin, and dactinomycin. Despite a great deal of 'rational design' of synthetic DNA-intercalators has been achieved by researchers, only few compounds have proved clinically successful. The design and synthesis of new drugs is focused on intercalators which have two intercalating groups linked via a variety of ligands, and synergistic drugs, which combine the anticancer properties of intercalation [141]. The heterocycles such as thiazole-containing compounds fused with some other heterocycles have possessed DNA intercalating properties which is summarized as below. In vitro antiproliferative activity of a novel series of arylidene-hydrazinyl-thiazole-containing compounds was depicted by Grozav et al. against MDA-MB231 and HeLa cancer cell lines using MTT assay. Generally, the viability of cancer cell lines decreased as the concentration increased. Among the test compounds, 2-(2-benzyliden-hydrazinyl)-4-methylthiazole derivative (97a) was highly potent against both the cell lines MDA-MB-231 (IC50; 3.92 µg/ml) and HeLa (IC50: 11.4 µg/ml) than the standard chemotherapeutic cisplatin (IC50; 17.28, 26.12 µg/ml) and oxaliplatin (IC50; 14.09, 23.17 µg/ml), respectively. Further, DNA Intercalation study was conducted on compounds (97a-97d) through the gel electrophoresis experiment which indicated that antiproliferative activity of these derivatives against MDAMB231 and HeLa cancer cell lines is independent of DNA intercalation [142]. 9-Anilinothiazolo[5,4-b]quinoline derivatives for their in vitro cytotoxic activity and DNAintercalation studies were evaluated by Reyes-Rangel et al. The cytotoxic activity was 39
performed against one cervical cancer line (HeLa), two colorectal cancer cell lines (SW-480 and SW-620) and one leukaemic cell line (K-562). Generally leukaemic cell line (K-562) and cervical cancer line (HeLa) were more susceptible towards the test compounds within a IC50 values range of 5.69-85.8 µM. Among the test compounds, compound (98) exhibited maximum activity against K-562, while against HeLa compound (99) was most effective with IC50 values of 4.5 and 12.06 µM, respectively. By studying the substitution pattern, it was observed that substitution with methylthio group improves the intercalation of the derivatives into the DNA, but did not render the cytotoxic activity of the compound [143]. Two mononuclear copper (II) terpyridine complexes namely, [Cu(Btptpy)(ClO4)](ClO4) 100a, and [Cu(Bttpy)(ClO4)](ClO4) 100b, Btptpy (L1) = 4’-(Benzothiophene)-2,2’:6’,2”terpyridine, Bttpy (L2) = 4’-(Benzylthiazolyl)-2,2’:6’,2”-terpyridine) were developed by Manikandamathavan et al. in order to find out their antiproliferative activity against HEPG2 and triple negative CAL-51 cell line. The IC50 value of the two complexes have been found to be 0.28 ± 0.01 µM (100a) and 0.29 ± 0.01 µM (100b) in the case of CAL-51 cell line in comparision to cisplatin (8.22 µM). In addition, complexes (100a) and (100b) showed more cytotoxic effect with IC50; 0.31±0.03 µM (100a) and 0.27±0.01 µM (100b) on HEPG2 than the cisplatin (24.29 µM). DNA interaction studies showed that both the complexes bind DNA via intercalation [144]. Ar HC N
Compd.
R1 N N H
S
Active compound 97a; Ar; Phenyl; R1; CH3, R2; H IC50; 3.92 µg/ml
R2
(97)
N
S
R2
CH3 C6H5 CH3 C6H5
H H H H
X
S N
S
NH
N
N
N Cl (98)
R1
NH
N
N
C6H5 4-OCH3C6H4 4-OHC6H4 4-OHC6H4
97a; 97b; 97c; 97d;
N
Cl
Ar
(99)
Cu (ClO4) (100)
N Compd.
X
100a; 100b;
H N
Figure 26: Thiazole derivatives as DNA intercalating agents (97-100). 2.3
Miscellaneous anticancer activity of thiazole-containing compounds 40
Besides different modes/site of action, a number of thiazole-containing compounds have been screened for their antiproliferative/cytotoxic activity against numerous cancer cell lines such as breast cancer (MCF-7), lung cancer (HeLa), cervix cancer (KB/HELA), ovarian carcinoma (SK-OV-3), brain cancer (SF-268), nonsmall-cell lung cancer (NCl-H460), adenocarcinoma colon cancer (RKOP-27), Neuroblastoma (SKNMC), Human hepatocarcinoma (Hep-G2), human colon carcinoma (HT-29), breast carcinoma (BT-20) and leukaemia (CCRF-CEM) cells, etc. A series of steroidal derivatives possessing a D-ring substituted benzamidothiazole were synthesized by Fan et al. in order to find out their anticancer activity against PC-3 (human prostate cancer cell line) and SKOV-3 (ovarian cancer cells). All the screened derivatives demonstrated mild to moderate antiproliferative activity. Among the tested derivatives, (101) showed the maximum activity with 59% inhibition at concentration of 50 µM against d SKOV-3 cells in comparison to reference compound etoposide (VP-16) [145]. Kavitha et al. scrutinized 2-(4-(2-oxo-2H-chromen-3-yl)thiazol-2-yl)-3-arylacrylonitriles for their in vitro anti-hepatoma activity against HepG2 cell lines. Most of the compounds exhibited good to excellent cytotoxicity in HepG2 cells. Compounds (102a) and (102b) were found to possess excellent inhibition having IC50 values of 2.33 ± 0.004 and 2.89 ± 0.004 µM, respectively. Further, docking with B-Cell Lymphoma-2 (BCL-2) domain revealed that compound (102a) have shown one hydrogen bond interaction with BCL-2 domain with highest docking score of 57.22 k.cal/mol and bond length of 1.325 Å [146]. Mohammadi-Farani et al. introduced a series of N-phenyl-2-p-tolylthiazole-4-carboxamide derivatives and assessed their in vitro anticancer activity against human cancer cell lines such as Neuroblastoma (SKNMC), Human hepatocarcinoma (Hep-G2) and Breast cancer (MCF-7 cell) using doxorubicin as standard. All the test compounds were unable to yield anticancer activity against MCF-7 cell line. Only compounds (103a) bearing para nitro (IC50; 10.8 ± 0.08 µM) and (103b) bearing meta chlorine (IC50; 11.6 ± 0.12 µM) pharmacophoric features showed maximum cytotoxic effects towards SKNMC and Hep-G2 cell lines respectively [147]. Zablotskaya et al. have introduced a new series of N-[1,3-(benzo)thiazol-2-yl]-ω-[3,4dihydroisoquinolin-2(1H)-yl] alkanamide derivatives and evaluated them against monolayer tumour cell lines: human fibrosarcoma (HT-1080), mouse hepatoma (MG-22A), and normal mouse fibroblasts (NIH 3T3). From the SAR viewpoint, compound (104) was most effective 41
against hepatoma MG-22A with LC50 4 µg/ml (NO-induction ability and non-toxic at LD50 517 mg/kg) and moderately active against fibrosarcoma HT-1080. Whereas, halogen substituted compound was most active against human fibrosarcoma (HT-1080) (NOinduction ability and non-toxic at LD50; 1879 mg/kg). Substitution in compound (105c) with bulky groups, such as p-CH3O-C6H4 at C4 position of thiazolyl ring possessed positive effect on antitumour activity (LC50; 28 µg/ml) [148]. A microwave assisted synthesis of a novel series of sulfones of a 5-nitrothiazoles and their in vitro antiproliferative activity against two different cancer cell lines, CHO and HEPG2, was performed by Cohen et al. All the test compounds exhibited substantial inhibition against HEPG2 cells (7.7 µM ≤ HEPG2 CC50; ≤ 25.6 µM) as compared to standard drug doxorubicin (HEPG2 CC50 = 0.2 µM). Compounds (106a-106e) (dichlorinated) possessed high cytotoxicity against both the cell lines at (1.0 µM ≤ CC50 ≤ 2.5 µM) than dihydrogenated derivatives when compared with doxorubicin. Biological screening data clearly indicated that the methyl group next to sulfonyl attributied antiproliferative activity in this series against human liver tumour cells [149]. Antitumour activity of
two novel series of nortopsentin analogues of thiazolyl-bis-
pyrrolo[2,3-b]pyridines and indolyl-thiazolyl-pyrrolo[2,3-c]pyridines against the NCI-60 cell line panel was performed by Carbone et al. Primarily all the compounds were evaluated against approximately 60 human tumour cell lines derived from 9 human cancer cell types at a single dose 10-5 M. Further compounds (107) and (108) were selected and screened at five concentrations 10-4 M-10-8 M. Biological data showed that compounds (107) and (108) exhibited antitumour activity with GI50 values ranging from (0.81–27.7 and 0.93–4.70 µM respectively). Generally, indolyl-thiazolyl-pyrrolo[2,3-c]pyridine derivative (108) was more potent than thiazolyl-bis-pyrrolo[2,3-b]pyridines derivative (107). The cell cycle alteration mechanism suggested that (107) caused a dose-dependent and (108) induced a dosedependent accumulation of cells in G2/M phase [150]. A novel series of 2-phenyl-4-trifluoromethyl thiazole-5-carboxamide derivatives for their anticancer activity against A-549, Bel7402, and HCT-8 cell lines were executed by Cai et al. All the synthesized derivatives exerted moderate inhibition at 5 µg/ml when compared with standard drug 5-fluorouracil. Out of the test compounds, compound 4-chloro-2methylphenylamido substituted thiazole (109) bearing 2-chlorophenyl group on heterocyclic
42
moiety, showed highest activity (48%) against A-549 as compared to standard drug (57%) [151]. Various N-benzyl substituted (((2-morpholinoethoxy)phenyl)thiazol-4-yl)acetamide clubbed thiazole-containing compounds were synthesized by Fallah-Tafti et al. and subjected for Src kinase inhibitory activities and for anticancer activities against human colon carcinoma (HT29), breast carcinoma (BT-20) and leukaemia (CCRF-CEM) cells. Biological findings revealed that compound (110a) with GI50 values of 1.34 µM and 2.30 µM against NIH3T3/cSrc527F and SYF/c-Src527F cells, compound (110b) in the inhibition of cell proliferation of BT-20 and CCRF cells at concentration of 50 µM were found to be the most potent compounds. From SAR viewpoint, the presence of a substituent at position 4 of benzyl ring such as 4-F, 3,4-dicl2, or 4-CH3 were essential for strong anticancer activity [152]. Taher et al. have introduced some novel heterodiazole annulated imidazo[2,1-b]1,3,4oxa/thiadiazolone, 1,3,4-oxa or thiadiazole[3,2-a]pyrimidine diamine and 1,3,4-oxa or thiadiazole-3- piperidino-1-propamide derivatives. In vitro antitumour activity was carried out against a panel of 60 cell lines at concentration ranges of 0.01 to 100 µM. Out of test compounds,
compound
2-phenyl-7,7a-dihydro-imidazo[2,1-b][1,3,4]thiadiazol-5(6H)-one
(111) showed broad-spectrum antitumour activity having effectiveness toward numerous cell lines and was most active compound of this series with GI50, TGI, and LC50 values of 6.0, 17.4, and 55.1 µM, respectively, when compared with standard drug 5-flurouracil [153]. A series of cantharidin analogues with a structure of aminothiazole and anhydride were evaluated by Yeh et al. for their anticancer and cytotoxic effects on human hepatocellular carcinoma cell (HCC) lines HEPG2, Sk-Hep1 and then compared with primary cultured rat hepatocytes. All the screened derivatives exhibited no cytotoxicity against primary cultured rat hepatocytes as compared to their parent compounds. Of these, anhydride derivative promoted apoptosis in HEPG2 (IC50; 62 µM) and SK-Hep1 (IC50; 151 µM) cell lines. However thiazole derivative (112) was able to promote apoptosis in HEPG2 (IC50; 92 µM)
43
O HN O
N
Active compound 102a; R; -OCH3 IC50; 2.33 µM
N
N
F
S
S Compnd. 102a; 102b;
(101)
R
O
Compd.
N
NH
N(CH2)nCONH
Compd. 105a; 105b; 105c; 105d; 105e; 105f;
N
N (105)
R
(104) Cl Cl S N O R
O
S
CH3
Compd.
(106)
R p-NO2 m-Cl
R
n
S
S
O2 N
103a; 103b;
CH3
(103)
N(CH2)CONH
(102)
S
R
Active compound 103a; R; p-NO2 IC50; 10.8 µM
O
O
R
4-OCH3 3,4-diOCH3
R
106a; 106b; 106c; 106d; 106e;
Active compound 105c; R; p-CH3O-C6H4 LC50; 28 µg/ml
1 1 1 1 . HCl 2 2
Br
C6H5 p-CH3-C6H4 p-Cl-C6H4 p-Br-C6H4 p-F-C6H4
Active compound 106b; R; p-CH3-C6H4 CC50; 1.0 µM
H CH3 p-CH3OC6H4 p-CH3OC6H4 H p-CH3OC6H4
S N
N N
N
HN
Br
CH3 (107)
N S Cl N
F N
HN
F
NH
(108)
F NH
S Cl
O O
O
O
N N
Cl
S
(109)
N N H
S
N
(111)
O N
N O
S (110)
H N O
(112) R
Compd.
R
110a; 110b;
H F
Figure 27: Thiazole derivatives as cytotoxic agents (101-112). cell lines. Both the compounds anhydride and (112) were found to have similar anticancer effect. The SAR study concluded that removal of the bridging ether oxygen on the ring 44
decreased the hepatocyte cytotoxicity and the anhydride modified structure promoted apoptosis in human hepatocellular carcinoma cells [154]. A series of new imidazo[2,1-b]thiazole-containing compounds were scrutinized by Gursoy et al. in order to explore their potential for cytotoxic activity. For all the synthesized compounds preliminary anticancer assay was performed, subsequently compounds which passed the criteria for activity were further evaluated against the full panel of 60 human tumour cell lines at a minimum of five concentrations (10-fold dilutions). Amongest them, compound (113a) revealed noticeable effects on a prostate cancer cell line (PC-3, log10 GI50 value < 8.00). Structure analysis showed that 4-hydroxy substitution on phenyl group of compound (113a) contribute most active compound in series. However, movement of hydroxyl group from 4th position to 2nd position on phenyl ring leads to (113b) which demonstrate anticancer activity against most of the cell lines [155]. Prasanna et al. have designed and synthesized a series of 2-arylcarboxamide substituted (S)6-amino-4,5,6,7-tetrahydrobenzo[d]thiazole-containing compounds and screened for their anti-leukaemic activity against human leukemia cells, K562 and CEM at 10, 50 and 100 µM. Among the test compounds, compound (114) having a tert-butyl substitution at para position showed excellent inhibition against K562 and CEM cells with IC50 values of 4.52 µM. Further compound (114) was assessed for cytotoxic activity against 293T cells (human embryonic kidney epithelial cells). From the observation of their structures and SAR, it was concluded that compounds with ortho substitution or no substitution or substitution with bulky groups exhibited poor inhibition of anti-leukaemic cells, while compounds with substitution at meta and para positions showed reasonable inhibition of anti-leukaemic cells [156]. Synthesis of a novel thiazolone-based compounds containing 5-aryl-3-phenyl-4,5-dihydro1H-pyrazol-1-yl moiety as potential anticancer agents was done by Havrylyuk et al. Most of the synthesized compounds showed promising anticancer activity on leukemia, melanoma, lung, colon, CNS, ovarian, renal, prostate and breast cancer cell lines evaluated at single concentration of 10-5 M. Out of the test compounds, pyrazoline substituted derivative (115) containing di-methoxy along with hydroxyl groups on phenyl ring demonstrated highest activity on non-small cell lung cancer cell line HOP-62 and colon cancer cell lines HT 29 (having highest selectivity) with log GI50 - 6.37, and - 6.37, respectively. SAR study
45
concluded that substitution on 5th position of thiazolone ring and p-OH on benzylidene part improves the potency of the compounds [157]. Antitumour activity of various N-bis(trifluoromethyl)alkyl-N’-thiazolyl and -benzothiazolyl urea derivatives were depicted by Luzina et al. against several human cancer cell lines. Analogue (116) against UO-31 (renal cancer, log GI50 -5.66), and SR (leukemia, log GI50 5.44) of human cancer cells exhibited potent cytotoxic activity as compared to standard drug 5-fluorouracil, nonfluorinated urea and non-urea bis-trifluoromethylated benzothiazole [158]. Al-Omary et al. introduced a novel series of thiazolo[2,3-b]quinazoline, and pyrido[4,3d]thiazolo[3,2-a]pyrimidine and evaluated for their in vitro antitumour activity at 60 cell lines panel assay and compared with 5-FU standard drug. Biological findings indicated that compounds (117-119) revealed notable broad-spectrum antitumour activity. Out of them, compounds (117) and (118) were nine fold more active as compared to 5-FU (GI50, TGI, and LC50 values = 2.5, >100, >100 µM and 2.4, 9.1, 36.2 µM, respectively. On the other hand, compounds (119a) and (119b) were seven fold more active as compared to 5-FU (GI50, TGI, and LC50 values = 2.9, 12.4, 46.6 µM and 3.0, 16.3, 54.0 µM, respectively. From SAR viewpoint, the synthesized 6,7,8,9-tetrahydro-5H-pyrido[4,3-d]thiazolo[3,2-a]pyrimidine derivatives (117-119) were observed as more potent antitumour agents in comparision to their 6,7,8,9-tetrahydro-5H-thiazolo[2,3-b]quinazolines (117) counterparts [159]. Chen et al. have developed a new and efficient method for the synthesis of N-(2-chloro-6methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl)]-2-methyl-4-pyrimidinyl]-amino)]1,3-thiazole-5-carboxamide (120) popularly known as anticancer drug dasatanib. The reaction described a chemoselective α- bromination of β-ethoxyacrylamide followed by a one-pot treatment with thiourea to give 2-aminothiazole-5-carboxylamide in excellent yield. With this new method, they were able to avoid the generation and handling of the moisture sensitive organometallic intermediates and protection/deprotection steps [160]. Screening of several novel 5-arylidene-4-thioxo-thiazolidine-2-one derivatives for their antimicrobial activity and antiproliferative activities against two human carcinoma cell lines (NCI-H292 and HEp-2) was done by Gouveia et al. Generally, compounds (121), (122) were observed to be more sensitive to NCIH292 cell lines than the HEp-2 cell lines. However, these compounds demonstrated lower cytotoxicity as compared to vincristine standard drug (IC50; 0.04, 0.003 µg/ml for NCI-H292 and HEp-2, respectively). From the biological data 46
the antiproliferative activity was only observed at 45.03% (122g) for NCI-H292 cell lines and at 30.10% (122c) for HEp-2 cell lines. Furthermore, none of the compounds was able to produce 50% inhibition of cell proliferation at the highest dose (10 µg/ml) [161].
CH3 H3C CH3
R CH2CONHN=CH
H2N
N
N
Br N
Compd.
S
113a; 113b;
(113)
N H
O
(114)
4-OH 2-OH F
O
HO
OH
S
F CH3 O HN F HN
F F
CH3
O
N N N
S
R
F
S N
CH3
O
(116)
(115)
S N
S
N
N
OCH3
N
H3CO
OCH3
H3CO
OCH3
N H3C
OCH3 (117)
(118)
H3CO
R
S
S N
O N
H3CO
OCH3
H3CO H3C
(119)
Cl
CH3
N HO
N
R
119a; 119b;
H CH3
S
N H (121)
OCH3
N
N
Compd.
N
O
HN
N N H
Active compound 122g; R; 2-Cl Inhibitory Conc.; 10 µg/ml
S
Dasatanib (120)
OH C 3
HN S
S
(122)
R
Compd.
R
122a; 122b; 122c; 122d; 122e; 122f; 122g; 122h; 122i; 122j;
2-F 3-F 4-F 2-Br 3-Br 4-Br 2-Cl 3-Cl 4-Cl 2,4-Cl2
Figure 28: Thiazole derivatives as cytotoxic agents (113-122).
Various pyridazino-, pyrimido-, quinazolo-, oxirano- and thiazolo-steroidal derivatives were produced by Elmegeed et al. and screened for their potential chemotherapeutic anti-breast 47
cancer agents against human breast cancer cells (MCF-7). All the test compounds exhibited potent broad spectrum cytotoxic activity as compared to standard drug doxorubicin (Dox) (IC50; 4.5 µM) after 48 h incubation. Compound (123) displayed most potent inhibitory effect on MCF-7 growth with IC50; 2.5 µM than doxorubicin (IC50; 4.5 µM). Remarkably, compounds (123-124) showed significant depletion with various intensities in gene expression of breast cancer related genes (VEGF, CYP19 and hAP-2γ). From SAR viewpoint, the attachment of heterocyclic moiety such as thiazole to steroidal moiety leads to potent cytotoxic activity in compound (123) followed by the copper complexes compound (124) and pyrimidinyl androstane derivatives [162]. Several
novel
5-(2-Aminothiazol-4-yl)-4-phenyl-4H-1,2,4-triazole-3-thiol
containing
derivatives were synthesized and were screened for their anticancer activity by Hassan et al. Four human tumour cell lines namely: hepatocellular carcinoma HEPG2, caucasian breast adenocarcinoma MCF-7, colon carcinoma HCT-116, and lung carcinoma A549 were used to ascertain the potency of test compounds, while doxorubicin was used as standard drug. Compounds (125) and (126) were equipotent to doxorubicin with LC50 values of 17.4-25.0 µM against the four tumour cell lines. Compound (126) have emerged as most potent compound by exhibiting LC50 values of 23.5 and 17.4 µM against colon carcinoma HCT-116 and caucasian breast adenocarcinoma MCF-7 cell lines, respectively. It was concluded that substituent at the 2-amino group of the thiazole nucleus or at the 4-phenyl ring attached to the 1,2,4-triazole function have great influence on antitumour activity [163]. Hassan et al. introduced a novel series of 2-acetamido- or 2-propanamido-4-(4-substituted phenyl)-1,3-thiazole-containing compounds and tested for their in vitro antitumour activity at a single dose of 10 µM. Most of the test compounds showed significant antitumour activity at given dose than the standard antitumour drug 5-FU. Compounds (127a) and (127b) bearing the chloro group were the most potent anticancer agents which was about nine and seven fold potent with MG-MID GI50, TGI, and LC50 values of 2.8, 11.4, 44.7; and 3.3, 13.1, 46.8, respectively, as compared to standard drug. From the above findings, it was concluded that the three carbon chain connecting the thiazole nucleus to the secondary amines had significant influence on antitumour activity [164]. Several 2-substituted benzimidazoles consisting 2-[(4-oxothiazolidin-2-ylidene) methyl and (4-amino-2-thioxothiazol-5-yl) benzimidazoles; 2-[(4-fluorobenzylidene and cycloalkylidene) cyanomethyl] benzimidazoles; 2-[(4- or 5-oxothiazolidin-2-ylidene, 4-substituted thiazolyl-248
ylidene and [1,3]thiazin-2-ylidene) cyanomethyl] benzimidazoles were synthesized and screened for in vitro anticancer activity by Refaat et al. The anticancer activity was performed against human hepatocellular carcinoma cell line (HEPG2), human breast adenocarcinoma cell line (MCF-7) and colon carcinoma cell line (HCT-116) while doxorubicin was used as standard antitumour drug (10 µg/ml). Among the thiazolecontaining compounds, 2-thiazolylbenzimidazole derivative (128) and oxothiazolidin-2ylidenecyanomethyl benzimidazole (129) were the most potent compounds possessing broad spectrum of activity against all three cell lines with IC50 values of 0.55, 3.51, 4.23; 0.93, 2.83, 3.72 and IC90 values of 7.53, 14.06, 14.02; 7.89, 12.63, 12.02, respectively. In conclusion, all the test compounds were found to possess potential antitumour activities against all the tested tumour cell lines [165]. Fluorinated 2-(4-aminophenyl)benzothiazole analogues as a potential in vitro cytotoxic agents against various cell lines were introduced by Hutchinson et al. Generally these compounds showed better cytotoxic activity in the range of micromolar concentration as (GI50 < 1 µM). Biological evaluation revealed that compound (130) bearing 5-F substitution was potently in vitro cytotoxic (GI50 < 0.01 µM) against NCI cell panel (NCI-H266, NCIH460, HCC-2998, IGROV1, OVCAR-4, OVCAR-5, TH-10, MCF-7, T47-D). Interestingly, compound was metabolically stable and form no exportable metabolites in the presence of these cells, approving that oxidative metabolism of 2 in the 6-position completely blocked by 5-fluorination [166]. A new series of arylidene-hydrazinyl-thiazole-containing compounds was developed by Grozav et al. and were assayed for their in vitro antiproliferative activity against two human carcinoma MDA-MB231 and HeLa cell lines using MTT assay. According to IC50 data five thiazole-containing compounds have shown significant inhibition as compared to the standard drugs platinum drugs, cisplatin and oxaliplatin. Compound 2-(2-benzyliden-hydrazinyl)-4methylthiazole (131) against MDA-MB-231 (IC50; 3.92 µg/ml) and HeLa (IC50; 11.4 µg/ml), compound (132) with an IC50 value of 11.1 µg/ml against HeLa cell lines were emerged as potential leads and hence could be investigated for further scientific exploration for the treatment of cancer [167]. Some pyrazole-based 1,3-thiazole and 1,3,4-thiadiazole derivatives were synthesized and assayed for their in vitro anticancer activity by Dawood et al. These compounds were screened against human hepatocelluar carcinoma (HEPG2), human breast cancer (MCF-7) 49
and human lung cancer (A549) and compared with doxorubicin (0.877, 1.172, 0.41 µM respectively) standard drug. Among all the test compounds, the starting precursor i.e. compound (133) (8.348 10.08 7.743 µM) and 1,3,4-thiadiazole (134) (8.107 10.03 8.68 µM) of series were almost equipotent, exerting the pronounced anticancer activity. SAR studies have concluded that isosteric replacement between the compounds of the series control the anticancer activity [168]. In search of novel anticancer agents twenty one new benzothiazole bearing 2-thioxo-4thiazolidinone derivatives were synthesized by Mosula et al. and screened in vitro for anticancer activity at 60 human tumour cell lines. Newly synthesized compounds showed antitumour activity on renal cancer, non-small cell lung cancer, ovarian cancer cell lines. Out of the tested, compound 2-{2-[3-(benzothiazol-2-ylamino)-4-oxo-2-thioxo-thiazolidin-5ylidenemethyl]-4-chlorophenoxy}-N-(4-methoxyphenyl)-acetamide (135) was found to be most active with average logGI50 and logTGI values -5.38 and -4.45 respectively. Compound (135) was selected as matrix for further drug design of 4-thiazolidones as possible anticancer agents [169]. Desai et al. screened some thiazole clubbed 1,3,4-oxadiazole derivatives for their in vitro antimicrobial and cytotoxic activities. The antimicrobial activity results revealed that compounds (136a), (136b) (antibacterials) and (136c) (antifungal) were emerged as most potent lead compounds in the series displaying MIC 12.5-250 µg/ml. Further, in vitro cytotoxicity of compounds (136) were performed against human cervical cancer cell line (HeLa) by the MTT colorimetric assay. It was observed that none of the test compounds exhibited any significant cytotoxic effect on HeLa cells, which suggested that these compounds have a great potential for their in vivo use as antimicrobial agents [170]. Twelve novel 17-(2’-oxazolyl)-and 17-(2’-thiazolyl)-androstene derivatives were synthesized by Zhua et al. and assessed as inhibitors of 17 α-hydroxylase-C17,20-lyase (P45017α). Generally, the potent inhibitors of P45017α could be used in effective treatment of prostate cancer. The results showed that the compounds containing 17-(2’-oxazolyl) (56.0% inhibition) and 17-(2’-thiazolyl) (23.7%) demonstrated inhibition against P45017α, although they were less potent than ketoconazole. Compound 17-(5’-methyl-2’-thiazolyl) (137, 72.1%) had similar activity to ketoconazole and was as much as potent to 17-(5’-isoxazolyl)-pregna4,16-diene-3,20-dione (L-39) inhibitor among this series [171].
50
Mohareb et al. carried out synthesis of some naturally occurring pregnenolone containing thiophene, thiazole, thieno[2,3-b]pyridine derivatives. All the newly synthesized heterocyclic steroids were studied for their cytotoxicity against three human tumour cell lines namely breast adenocarcinoma (MCF-7), non-small cell lung cancer (NCI-H460) and CNS cancer (SF-268). Some of the test compounds showed much higher inhibitory effects than the standard drug doxorubicin (GI50 0.04 ± 0.008, 0.09 ± 0.008, 0.09 ± 0.007 µM). Among the test compounds, thiazole-containing compounds (138a), (138b) showed the highest inhibitory effect against MCF-7 (GI50; 0.6 ± 0.4, 0.2 ± 0.2 µM), NCI-H460 (GI50 0.2 ± 0.08, 0.6 ± 0.02 µM), SF-268 (GI50; 0.8 ± 0.4, 0.4 ± 0.08 µM), respectively. However cytotoxicity of the thieno[2,3-b]pyridinyl androstene derivatives was found much higher in the series [172]. In continuation to the search of novel anticancer agents Mohareb et al. synthesized some pyrazole, pyridine, thiazole and thiophene derivatives of pregnenolone. In vitro cytotoxic activity was executed against breast adenocarcinoma (MCF-7), non-small cell lung cancer (NCI-H460) and CNS cancer (SF-268). By comparing the cytotoxicity of the thiazolecontaining compounds (139a-139c), it was found that the 5-hydroxythiazole derivative (139c) has greater cytotoxicity against non-small cell lung cancer (NCI-H460, GI50; 0.01 ± 0.003 µM) and breast adenocarcinoma (MCF-7, GI50; 0.02 ± 0.001 µM) than the 5phenylthiazole derivative (139a) and the 5-methylthiazole derivative (139b), which was much higher than the standard drug doxorubicin (NCI-H460, GI50; 0.09 ± 0.008; MCF-7, GI50; 0.04 ± 0.008) [173].
51
CN
NO3
H3C
N S
HN
H
NO3 N
CN
(123)
(125) S
H
S
(124)
H
NH
HS Compd. 127a; 127b;
S Cl
R Cl CH3
N
(126)
NH2
H N
N
(127)
S
S
(128) S
N H3C
N
NH
S
N
N
N
OCH3
N N H
(131) (132)
NO2
CH3 N
H2N
NH2 S
S O
N
(130)
H3C
O
S N H
O
(129)
F
OH
N
N Cl
NH O
N
N
H N
N
N
O
Cl
O
O
H AcO
N
N
CH3
S
H
H
HS
CH3
N
N
N
H
AcO
S
NH2 Cu NH2
H
O
N S
(133)
O
H3C
N
N
N N
N S
N N
S
O
CH3
O
N
O
H3C
CH3
CH3
(134)
O S
N H O
S S
Cl
N N H (135)
O
H N
S N
R
O N
S N N H3C
Compd. 136a; CH3 136b; 136c; O
H N
R F OCH3 NO2
(136)
Figure 29: Thiazole derivatives as cytotoxic agents (123-136). Using key intermediates 1-(5 amino-3-hydroxy-1H-pyrazol-1-yl)-2-chloroethanone and 3-(5amino-3-hydroxy-1H-pyrazol-1-yl)-3-oxopropanenitrile some thiophene, pyran, thiazole and fused heterocyclic derivatives were synthesized by Mohareb et al. The in vitro antitumour activity was assessed against breast adenocarcinoma (MCF-7), non-small cell lung cancer (NCI-H460) and CNS cancer (SF-268) while doxorubicin was used as standard drug. Among the newly synthesized pyrazole-thiazole-containing compounds 2-(4-(5-amino-3-hydroxy52
1H-pyrazol-1-yl)-3-phenylthiazol-2(3H)-ylidene)-malononitrile (140a) and 2-(4-(5-amino-3hydroxy-1H-pyrazol-1-yl)-3-phenylthiazol-2(3H)-ylidene)-pentan-2,4-dione (140b) exhibited most potent inhibitory effects with GI50 0.01-0.03 µM [174]. In an another investigation Mohareb et al. utilized hydrazide-hydrazone for the synthesis of coumarin, pyridine, thiazole and thiophene derivatives and performed their antitumour activity against breast adenocarcinoma (MCF-7), non-small cell lung cancer (NCI-H460) and CNS cancer (SF-268).
Biological findings revealed that the thiazole derivative (141)
possessed moderate antitumour activity as compared to the standard drug doxorubicin (MCF7, GI50; 42.8 ± 8.2 nM; NCI-H460, GI50; 94.0 ± 8.7 nM, and SF-280, GI50; 94.0 ± 7.0 nM) [175]. A series of some novel 2-(benzo[d]thiazol-2-yl)-8-substituted-2H-pyrazolo[4,3-c]quinolin3(5H)-ones was synthesized by Reis et al. and screened for their in vitro antiproliferative activities against four human cancer cell lines: (MDA-MB-435) breast, (HL-60) leukemia, (HCT-8) colon and (SF-295) central nervous system. Biological findings revealed that compounds (142a) and (142b) displayed excellent cytotoxicity against three cell lines with IC50 values lower than 5 µg/ml. While, none of the compound exhibited haemolysis in mouse erythrocytes up to 250 µg/ml. Thus, it can be concluded that the most active compound (142b) against breast cancer (MDA-MB-435) can be used as a promising lead molecule for anticancer drug design [176]. Chaniyara et al. identified a new series of 2,3-bis(hydroxymethyl)benzo[d]pyrrolo[2,1b]thiazoles and their bis(alkylcarbamate) derivatives and assessed for their in vitro antiproliferative activity against human leukaemia and various solid tumour cell growth. Among the newly synthesized derivatives, compounds (143-145) displayed potent therapeutic efficacy against MX-1 in xenograft model, which was used for further evaluation of anticancer activity. Compounds (143-145) were shown to have most significant cytotoxicity with IC50 values of 0.07, 0.05 and 0.08 µM, respectively, against CCRF-CEM cell growth. The compounds showed complete tumour remission at a dose of submaximal tolerated dose of 20 mg/kg, and were selected as a lead compound for studying its anticancer activity [177]. A novel one-pot procedure for the synthesis of 2-(N-pyrrolidinyl)-4-amino-5-(3’,4’,5’trimethoxybenzoyl)thiazole have been developed by Romagnoli et al. The compounds were studied for their antiproliferative effects against murine leukaemia (L1210) and mammary carcinoma (FM3A) lines and the human T-leukaemia lines Molt/4 and CEM and the human 53
cervix carcinoma HeLa line. Only compound (146) exhibited submicromolar antiproliferative activity (GI50 0.18-0.37 µM) against all tested lines, whereas other derivatives generally had little activity (GI50 >10 µM) than the reference compound CA-4 (GI50 0.002-0.042 µM) [178]. Some novel benzoxazole derivatives were synthesized and assessed for their in vitro anticancer, anti-HIV-1 and antimicrobial activities by Rida et al. Antitumour activity was carried out against 60 human cell lines derived from nine clinically isolated cancer types (Leukaemia, non-small cell lung, colon, CNS, melanoma, ovarian, renal, prostate and breast cancer) at different concentrations. Comparing the antitumour activity of benzoxazole bearing thiazole-containing compounds (147a) and (147b), demonstrated potent activity against maximum tumour cell lines (GI50; TGI; and LC50; values < 100 µM & having selectivity ratio of 0.22-1.16). Specifically compound (147c) was most effective against CNS (GI50 values 21.5 and 12.9 µM), leukemia K-562 (GI50, 0.47 µM) and melanoma UACC-62 (GI50 0.45 µM) cancer cell lines. While, compound (147a) exhibited most potent antitumour activity against prostate cell line (GI50, 17.9 µM) [179]. Synthesis of some novel 1,3,4-oxadiazole derivatives containing different pharmacophores/ heterocyclic rings for antitumour and cytotoxic activities was executed by Bondock et al. The newly developed compounds were screened against four cancer cell lines (namely HEPG2, WI-38, VERO, MCF-7) and some of them exerted promising in vitro antitumour activity. The resultant data suggested that incorporation of a thiazole ring in compound (148) to 1,3,4oxadiazole skeleton displayed improved antitumour activities than the pyrazole and thiophene ring systems. Compound (148) demonstrated most potent activity against lung fibroblasts (WI 38; GI50 17.3 µg/ml), hepatocellular carcinoma (HEPG2; GI50 12.4 µg/ml), kidney carcinoma (VERO, GI50; 15.8 µg/ml) and moderate activity against breast cancer (MCF-7; GI50; 26-50 µg/ml). Besides, compound (148) exhibited high protection against DNA damage induced by the bleomycineiron complex, thus diminishing chromogen formation between the damaged DNA and TBA [180].
54
R
CH3
N S
CH3
Compd.
R
138a; 138b;
Cl Br
N N N
CH3
S
HO
(138)
OH
(137)
R1 HO
Compd.
R
139a; 139b; 139c;
O
Ph CH3 OH
HN N
N N
N
R2
S
CN
NH2
(140)
S CH3
Active compound 139c; R; OH GI50; 0.01µ µM
N
Ph
R
Compd.
R1
140a; 140b;
CN CN
R2 COCH3 COCH3
(139)
HO
N
NH
O
O
Compd. S
N H
S
N
N
R
142a; 142b;
CH3
S
N
H2N
N
N
CH3 Br
(142) Cl
(141) F HO O
H3C CH3
H3C
H3C O
N N
N S
H3C HO
OH
N O
N CH3
O
N
O OH CH3
(143)
OH O
N S
H3CO
N
O
CH3
O H3C H2N
N (146)
CH3
(145)
OH CH3
F Active compound 147c; R; 4-ClC6H4 GI50; 0.45 µΜ
H2N N
N
OH CH3
CHO S
S O
N
(144) H3CO
O
N
N O
OH
N
HO HO
CH3
O N (147)
N S
R S
Compd.
R
147a; 147b; 147c;
(CH2)3CH3 CH2C6H5 4-ClC6H4
Figure 30: Thiazole derivatives as cytotoxic agents (137-147).
55
The
anticancer
activity
of
novel
2-[(2-oxo-2H-[1,2,4]triazino[2,3-c]quinazolin-6-
yl)thio]acetamides with thiazole and thiadiazole fragments were inspected by Kovalenko et al. The cytotoxic activity evaluation was done by means of bioluminescent test of the luminescent bacteria Photobacterium leiognathi at the concentration gradient of 0.025-0.25 mg/ml. Preliminary in vitro anticancer assay was performed against a panel of 60 cancer cell lines derived from nine different cancer types: leukemia, melanoma, lung, colon, CNS, ovarian, renal, prostate, and breast cancers at a fixed concentration of 10 µM. Among the test compounds, compound (149) possessed potent anticancer activity against the cell lines of colon cancer (GI50 0.45-0.69 µM), melanoma (GI50 0.48-13.50 µM) and ovarian cancer (GI50 0.25–5.01 µM) with most favourable selective index 3.16 against ovarian cells [181]. Some indeno[1,2-c]- pyrazol(in)es substituted with sulfonamide, sulfonylurea(-thiourea) and some derived thiazole ring systems were synthesized by Rostom et al. The newly synthesized compounds were assayed for their in vitro antitumour activities against 60 cell lines of nine tumour subpanels, including leukaemia, non-small cell lung, colon, CNS, melanoma, ovarian, renal, prostate and breast cancer cell lines. Among the thiazole-containing compounds (150) and (151) showed potential broad spectrum antitumour activity and low selectivity index against almost all the tested subpanel tumour cell lines (GI50 < 100 µM). However, 4-(3-(4chlorophenyl)-4H-indeno[1,2-c]pyrazol-2-yl)-benzenesulfonamide having no thiazole moiety in its structure; proved to be the most effective analog with the utmost cytostatic and cytotoxic potentials (TGI and LC50 (MG-MID) concentrations of 33.1 and 66.1 µM, respectively). Generally, the oxidized pyrazoles exhibited superior antitumour activity than their parent pyrazoline analogs [182]. Laczkowski et al. developed some thiazole-based nitrogen mustard and screened them as anticancer agents against human cancer cells lines (MV4-11, A549, MCF-7 and HCT116) and normal mouse fibroblast (BALB/3T3). Among the derivatives, 152a, 152b, 152c, 152d and 152e were found to exhibit high activity against human leukaemia MV4-11 cells, with IC50 values of 2.17-4.26 µg/ml. While, compounds (152c) and (152e) showed strong activity against MCF-7 and HCT-116 with IC50 values of 3.02-4.13 µg/ml. Compound (152c) was 5-8 times lower toxic against normal mouse fibroblast BALB/3T3 cells than against cancer cell lines. The molecular modelling studies revealed that possibility of human topoisomerases inhibition might be the mechanisms which attributed the anticancer activity of these derivatives [183].
56
As a part of ongoing studies in developing new anticancer agents, a series of bifunctional ethyl 2-amino-4-methylthiazol-5-carboxylate derivatives were synthesized by Rostom et al. and evaluated for their preliminary in vitro antimicrobial and anticancer activities. Out of the test compounds, nine were evaluated for their in vitro anticancer activity against NCI 60 cell panel including leukemia, non-small cell lung, colon, CNS, melanoma, ovarian, renal, prostate and breast cancer cell lines at fixed dose of 10 µM. The results revealed that, compound (153) proved to possess a broad spectrum of anticancer activity against 29 of the tested 60 subpanel tumour cell lines, particularly effective against the non-small cell lung cancer (Hop-92), ovarian cancer (IGROV1) and melanoma (SK-MEL-2) cell lines (GI% 64.2, 72.9 and 77.6, respectively). From SAR viewpoint, it was found that derivatization of the 2-amino group, rather than the conversion of the ester function into carboxamido and acid hydrazide moieties imparts superior cell growth inhibitory activity [184]. Kok et al. introduced novel cantharimide analogues bearing 2-aminobenzothiazole in order to find out their cytotoxicity on SK-Hep-1 hepatoma cells. Compound (154a) (CAN036) showed a comparable MTS50 activity (50% of MTS reduction ability, 3-6 µg/ml) as that of cantharidin (MTS50 = 6.25-12.5 µg/ml) and cisplatinum (MTS50 = 6.25–12.5 µg/ml) on SKHep-1 hepatocellular carcinoma cell line. While compound (154b) bearing methyl group demonstrated a weaker activity against cancer cell line (MTS50 = 12.5-25 µg/ml). SAR studies demonstrated that the introduction of electron withdrawing group of 2aminobenzothiazole at 6-position attributed to enhanced cytotoxicity to cancer cells whereas reducing the non-malignant cell toxicity [185]. Thiazol-5-carboxamide derivatives were scrutinized by Cai et al. in order to explore their potential as anticancer agents against A-549, Bel7402, and HCT-8 cell lines. Out of test compounds, 4-chloro-2-methylphenyl amido substituted thiazole containing the 2chlorophenyl group on 2nd position (155) of the heterocyclic ring displayed highest activity (48% inhibition) against A-549 as compared to standard drug 5-fluorouracil (57% inhibition) at a concentration of 5 µg/ml. The title compounds exhibited no inhibition or low inhibitory effect against Bel7402 and HCT-8. Only compound (156) (40% inhibition) displayed moderate inhibitory activity against HCT-8 [186]. Liu et al. presented a novel modified chiral 2-(ethylthio)-thiazolone derivatives and evaluated for their in vitro anticancer activities against five different cancer cell lines using the MTT assay. Most of the synthesized derivatives have shown potential anticancer activities against 57
EJ, PC-3, HepG-2 and Jurkat cancer cell lines with an IC50 range of 20-30 µM. Out of these test compounds, compounds (157a) and (157b) having one ortho-halogen substituted on phenyl group showed noteworthy inhibitory effects on the Jurkat with IC50 values of 17 and 19 µM, while a weaker inhibitory activity (IC50; 38 µM, 41 µM) on the breast cancer cell MDA-MB-231 was reported [187]. A small library of enantioselective largazole analogs was developed by Zeng et al. in order to assess their antiproliferative activity against HCT-116, A549, HEK293 and HLF cancer cell lines at a concentration of 10 µM. Generally, no activity was found with cis geometry of the alkene against either human tumour cell lines or normal cell lines. Compounds (158a) and (158b) were equipotent to largazole against normal cell lines, while in compound (158c) the replacement of Val 1 with tyrosine produced much improved selectivity for cancer cell lines (HCT-116: GI50 0.39 µM; A549: GI50 1.46 µM) over the normal cell lines (HEK293: GI50 > 100 µM; HLF: GI50 >100 µM). The resultant data suggested that the tyrosine residue of compound (158c) could be responsible for the selectivity towards cancer cells over normal cells [188]. Shi et al. screened twenty novel benzothiazol-2-thiol derivatives for their in vitro anticancer activity against a panel of different types of human cancer cell lines. Among the screened derivatives, pyridinyl-2-amine linked benzothiazol-2-thiols exhibited potent and broadspectrum inhibitory activities. Compound (159a) exerted highly potent anticancer activity on SKRB-3 (IC50;1.2 nM), SW620 (IC50; 4.3 nM), A549 (IC50; 44 nM) and HEPG2 (IC50; 48 nM) about 10-1000 times potent than the standard. Further, compound (159a) induced apoptosis in HEPG2 cancer cells. However, against A431 (IC50; 20 nM) compound (159b) exhibited the most potent antitumour activities from the series [189]. Mabkhot et al. developed biologically important thieno[2,3-b]thiophene derivatives and evaluated for their in vitro β-glucuronidase and α-glucosidase inhibitory activities, DPPH radical scavenging activity, cytotoxicity and anticancer activity. Comparing the anticancer activity of thiazole-containing compounds, compound (160) exhibited moderate anticancer activity with (IC50; 24.213 ± 0.29 µM) against PC-3 cell lines as compared to standard drug doxorubicin (IC50; 0.912 ± 0.12 µM). All the other screened compounds were observed to be non-cytotoxic and showed >30% inhibition of PC-3 cancer cell lines [190].
58
O
NC S
H3C
O
N N
N
CH3
N
N N
N H
O
N N
N S
S
N O
(148)
N
N S O2
HN
(149)
O
S
(150) Cl
N N
N
N S O2
HN Active compound 152c & 152e; IC50; 3.02-4.13 µg/ml
S Cl Cl
(151)
HN S
N Compd.
R1
N O S N O H
N NH (152)
Compd.
N S (154)
R O
NH
OCH3 CH3
S S
N
F3C
N
CH3
(157)
Compd.
R
157a; 157b;
Cl Br
(155)
O
S
R
O
N
N
Cl
H N
S
CH3
(156)
Cl
O
HN Ts
Cl
S NH H N
Cl
N
S
Cl
4-F 4-CN 4-CF3 4-OCH3 2,3,4,5,6-F5
R
154a; 154b;
R
O
O CH3
(153) CH3
O CH3 N
F3C
R1
152a; 152b; 152c; 152d; 152e;
CH3
O
O O
N
O
Cl
S
O
NH (159)
Compd. 158a; 158b; 158c; H3C
O
R CH(CH3)2 C6H5 4-OH-C6H4
R O
O S
S NH O
N O
N
S
Compd.
R
159a; 159b;
Br Cl
N H
(158)
Figure 31: Thiazole derivatives as cytotoxic agents (148-159). New rhodacyanine analogues containing the pyridinium, isoquinolinium and quinolinium ring system were developed by Li et al. and assessed for antitumour activity against human lung cancer cell line (H460). Nearly every tested compound exhibited superior antitumour activity with IC50 values ranging from 0.006-9.2 µmol/l as compared to the lead compound 59
MKT-077. Among the test compounds, the most promising compound (161) (IC50; 0.006 µmol/l) was found to be 216.7 times more active than MKT-077 (IC50; 1.3 µmol/l). SAR study concluded that change in the heteroaromatic ring linked to the rhodanine ring via N–N covalent bond enhanced the antitumour activity following the order: quinolinium > isoquinolinium > pyridinium. While, replacing the substituent methyl to cyclopropyl groups on the rhodanine ring, and hydrogen to chloride groups on 6th position of benzothiazole ring have little or no influence on antitumour activity [191]. Luo et al. presented a novel series of thiazolylbenzimidazole derivatives and scrutinized for their antitumour activity against SMMC-7721 and A549 cell lines. Generally, all the known derivatives demonstrated excellent antitumour activity. One compound, (162) containing a flexible and basic alkyl chain showed significant in vitro anticancer activity against both SMMC-7721 cell (IC50; 1.14 µM) and A549 cell (IC50; 2.43 µM) comparable to taxol (IC50; 1.42, 0.63 µM). Data suggested that thiazolylbenzimidazole compounds with no quinone moiety could also serve as potent antitumour agents [192]. Hybrids of macrosphelides and epothilones with a thiazole side chain were designed and assessed for antitumour and apoptosis-inducing activities by Matsuya et al. Some of these hybrid analogues having thiazole substituent were found to exhibit prominent apoptosisinducing activity against human lymphoma cells than parent natural macrosphelides. Among the thiazole containing compounds, compound (163) demonstrated most potent early apoptosis and negligible secondary necrosis at 1 µM concentration. Rest of all the screened derivatives were moderate to poor in apoptosis-inducing activity [193]. Kanda et al. contributed novel C-8 ester derivatives of leinamycin which exhibited significant antitumour activity against the several experimental models. It was found that number of ethylene glycol ether units (n) were essential for both in vitro & in vivo antiproliferative activity against HeLa S3 cells & sarcoma 180, respectively. Specifically, compound (164) showed significant antitumour activity against Lu-65 (T/C 0.20), against sarcoma 180 (T/C 0.30) [194]. Chakrabarty et al. have introduced regioselective synthesis of novel 2-alkylamino- and 2alkylthiothiazolo[5,4-e]- and -[4,5-g]indazoles and evaluated for their anticancer activity against A549 cell line. Biological study revealed that compound (165) exhibited most potent
60
activity (GI50 72.1 µmol, 78.8 µmol) at a concentration of 25 & 100 µmol, respectively against human lung carcinoma A549 cell line [195]. Cardoso et al. described new phthalimide derivatives endowed with dual immunomodulatory activity and antiproliferative activity. Antiproliferative activity was carried out against human cancer cell lines SF-295, HCT-8, MDA/MB-435 and LYMP at concentration of 50 µg/mL and lymphocytes at 5 µg/ml. Biological results have shown that compounds (166a) and (166b) were potent immunosuppressive agents with cell proliferation inhibition rates ranging from (IC50; 7.5, 5.3 µg/ml for SF-295) and (IC50; 5.8 and 5.2 µg/ml for HCT-8), respectively as compared to positive control doxorubicin. On the other hand, compounds (166a) and (166b) displayed IC50; 9.4 and 7.7 µg/ml, respectively, against human lymphocytes [196]. Soares et al. screened a new chiral 6-hydroxymethyl 1H, 3H-pyrrolo[1,2-c]thiazoles for their in vitro anticancer potential against colorectal adenocarcinoma, melanoma and breast adenocarcinoma cells. Among the test compounds, compound (167) possessed IC50; 62.9 µM, 15.4, 2.4 µM against A375 melanoma cells, WiDR colorectal adenocarcinoma cells and MCF-7 breast cancer cells, respectively. Similar results were obtained for 6-hydroxymethyl(R)-pyrrolo[1,2-c]thiazole benzylcarbamate (168) with IC50; 2.2 µM against MCF-7 breast cancer cell lines and IC50; 8.7 µM against colorectal adenocarcinoma cell lines. Thus, selectivity for breast cancer cell lines was observed for both pyrrolo[1,2-c]thiazole-containing compounds (167) and (168) [197]. Carbone et al. introduced nortopsentin analogues of thiazolyl-bis-pyrrolo[2,3-b]pyridines and Indolyl-thiazolyl-pyrrolo[2,3-c]pyridines and demonstrated their in vitro antiproliferative activity against the NCI full panel of human cancer cell lines and STO and MesoII cells, derived from human diffuse malignant peritoneal mesothelioma (DMPM). Among all the test compounds, compounds (169) and (170) exhibited antiproliferative activity against most of the human cell lines at GI50 values from micromolar to submicromolar (GI50 0.81-27.7 and 0.93-4.70 µM, respectively). Analogues (169) and (170) exhibited potent activity against human HTC-116 colorectal carcinoma cells and HCT-116 cells (GI50 2.91 and 2.35 µM,), (GI50 33.55 ± 2.31 µM and 13.15 ± 0.95 µM), respectively. Taking in account the GI50 values measured by NCI, the cytotoxic effects of the nortopsentin analogues appeared timedependent [198]. In an another study, Parrino et al. also identified a new series of nortopsentin analogues of 3[4-(1H-Indol-3-yl)-1,3-thiazol-2-yl]-1H-pyrrolo[2,3-b]pyridines and checked their in vitro 61
anticancer activity against various cell lines namely K-562, SR,NCI-H522, NCI/ADRRES,MDA-MB-435. The basic structure of nortopsentin contains the imidazole ring which was replaced by thiazole and indole moieties. Out of the tested analogues, analogues (171a171b) showed potent antiproliferative activity and high selectivity against 60 human tumour cell lines of NCI panel with micromolar to nanomolar GI50 13.0-0.03 and 14.2-0.04 µM, respectively. Both the compounds exhibited a concentration-dependent accumulation of cells in the sub G0/G1 phase while confined viable cells in G2/M phase [199]. Anticancer activity of a series of 2,4-disubstituted-1,3-thiazoles linked with pyrazoline scaffolds was done by Sadashiva et al. Anticancer activity was carried out against A549 and MCF-7 human cancer cell lines. Generally, the compounds bearing chloro atom at the para position of phenyl ring A such as (172-174) exhibited superior anticancer activity with IC50 values of 7.5, 5.0 and 5.0 µM respectively as compared to the standard drug cisplatin (IC50; 10.0 µM). Further, compounds were also evaluated for their in vitro antimicrobial activity and some of them possessed good activity against the strains used [200]. In a study, Mirza et al. have scrutinized several novel substituted aryl-thiazole (SAT) derivatives for their cytotoxicity against four cancer cell lines namely MCF-7 (ER +ve breast), MDA-MB-231 (ER –ve breast), HCT-116 (colorectal) and HeLa (cervical). Among them, compounds (175a-175b) demonstrated improved toxicity to the four cell lines with IC50 values 5.37 ± 0.56 to 46.72 ± 1.80 µM as compared to the standard drug doxorubicin (IC50; 1.56 ± 0.05 µM). The results revealed that substituted aryl thiazoles (175a) and (175b) might be a suitable lead compounds for further investigation in cancer treatment [201].
62
H3C
CH3
H2N
N
NH2
N
S
S
N+ IN
CH3 N S
S
S
S
H3C
N
N H
S
N
H3C
N
N
CH3
O
(160)
O
N
(162)
(161) O S
O
O
H3C
O N
-
O
O
O
H3C
CH3
S
S
O S+
(165)
N
O
OH
O H3C
H N
N
NH
S
O
N H
N
NH
(163)
N
N
O
O O
H3C O
O
CH3
HO
(164)
CH3
S O
Cl
Compd. 166a; 166b;
(166)
S
Cl OCH3
H N
H N
(167)
Br N
O
Br
N
S
O
Cl
S NH
N
(170)
CH3 N
N
N
N
H N HO
N
R
(169)
H N
S
S
O N H
N
N N
(168) H3C Compd.
R
171a; 171b;
CH3 H
Cl
N N N
N R
(172)
R1
Cl
S (171)
H N
S N
Cl
O N H
O
N N
O 2N
O
(173)
HN N
N N
S O Cl
N
HN NH
N (174)
O
R2
Compd.
R1
R2
175a; 175b;
2-NH2 4-Cl
4Cl 4-Br
S (175)
Figure 32: Thiazole derivatives as cytotoxic agents (160-175). Popsavin et al. reported new tiazofurin analogues bearing 2,3-anhydro functionality in the furanose ring and evaluated for their in vitro antitumour activity against various cell lines viz. 63
K562, HL-60, Jurkat, Raji, HT-29, MCF-7 and MRC-5. Remarkably, all three analogues (176-178) exhibit sub-micromolar cytotoxicity against K562 malignant cells, (IC50; 0.09 to 0.49 µM). Compound (176) and µ-homo-C-nucleoside (177) showed most potent cytotoxic activity against Raji cells, being almost 30-fold and 230-fold, respectively with respect to the reference compound tiazofurin. Compound α-homo-C-nucleoside (178) was most powerful antitumour agent against K562 cell line (33-fold) while inactive against Raji cells than tiazofurin (IC50; 16.02 µM). Interestingly, all these compounds were completely inactive against the normal MRC-5 cells [202]. Abdelgawad et al. executed synthesis and in vitro antiproliferative activity screening of certain novel thiazolidinone derivatives substituted with benzothiazole or benzoxazole. Newly synthesized compounds were scrutinized against human breast MCF-7 and liver HEPG2 cancer cell lines using doxorubicin (GI50 29.66 nM and 1.036nM) as a reference. pMethoxy- 5-benzylidine-4-thiazolidinone derivatives of benzoxazole (179a) (IC50; 0.027 nM) and benzothiazole (179b) (IC50; 0.026 nM) exhibited most potent antitumour activity against liver HEPG2 cancer cell line, respectively. On the other hand, compound (179c) against breast MCF-7 cancer cell line (IC50; 19 nM), while compound (179d) exhibited a broad spectrum antitumour activity against MCF-7 and HEPG2 cell lines with IC50; 36, 48 nM, respectively [203]. Some novel 1,3-thiazole-containing compounds containing hydrazide-hydrazone and carboxamide moiety were synthesized by He et al. Anticancer activity of synthesized compounds was carried out against MCF-7, HEPG2, BGC-823, Hela, and A549 cell lines using 5-Fu as standard drug. Some compounds exhibited superior activity, specifically, compounds (180a) and (180b) exhibit best cytotoxic activity with IC50 values of 2.21 µg/ml and 1.11 µg/ml against MCF-7, and HEPG2 cell lines, respectively. In addition, the flow cytometry analysis of compounds (180a, 180b) showed induced apoptosis in HEPG2 cells by S cell-cycle arrest [204]. Gomha et al. described a novel series of 3-[1-(4-substituted-5-(aryldiazenyl)thiazol-2yl)hydrazono)ethyl]-2H-chromen-2-ones for their in vitro cytotoxic activity against HaCaT cells (human keratinocytes). Among all the compounds, compound (181) possessed significant cytotoxic activity. MTT assay results of healthy cells HaCat cells incubated with 50 µL 0.5 mol compared to control compound (181) showed better time-dependent
64
cytotoxicity. However, the used concentration of (181) did not produce noteworthy cytotoxic effect on the healthy HaCaT cells [205]. In an another study, Gomha et al. examined some thiazoles, thiadiazoles, and pyrido[2,3][1,2,4]triazolo[4,3-a]pyrimidin- 5(1H)-ones incorporating triazole moiety for in vitro antitumour activity against MCF-7 and HEPG2 cell lines. The biological findings revealed that thiazole derivative (182) possessed potent antitumour activity against the human hepatocellular carcinoma cell line HEPG2 and the breast carcinoma cell line (MCF-7; IC50; 3.41 and 1.12 µM, respectively) while rest of the test compounds have shown moderate anticancer activities [206]. In continuation to the search of novel molecules to act as potential anticancer agents Gomha et al. reported coumarin derivatives containing pyrazolo[1,5-a]pyrimidine, tetrazolo[1,5a]pyrimidine, imidazo[1,2-a]pyrimidine, pyrazolo[3,4-d]pyrimidine, 1,3,4-thiadiazoles and thiazoles. Antiproliferative activities of newly synthesized compounds were done against various cell lines such as HSC-39, Caco-2 and Hep-G2. Resultant data of screened thiazolecontaining compounds revealed that compound (183) (with a chlorine atom as electronwithdrawing group on the aryl moiety) exhibited promising antitumour activity against liver carcinoma (HEPG2-1) with IC50 value of 3.50 ± 0.23 µM while rest of compounds showed moderate activity [207]. In an another study Gomha et al. introduced aryl azothiazoles and 1,3-thiazolidin-4-one derivatives and scrutinized for their in vitro antitumour activity against hepatocellular carcinoma HEPG2 cell lines using WST-1 proliferation assay. Out of the test compounds, compounds (184a-184c) have potent anticancer efficiency for hepatocellular carcinoma with low (IC50; 0.84 ± 0.04, 0.52 ± 0.03 and 0.5 ± 0.02 µM, respectively when compared to doxorubicin with molecular binding affinities of –24.85, –24.23, and –24.10 kcal/mol. The dose response curves of compounds (184b) and (184c) indicated the IC50 (the concentration of test compounds required to kill 50% of cell population) were 0.54 µM and 0.50 µM, respectively. Molecular docking results have showed that the groups like N=N, C=N, NH2 and OCH3 groups were most important for formation of the hydrogen bonds and hence for the enhanced anticancer activity [208]. Ghorab et al. reported synthesis of novel thiazolo[4,5-d]pyrimidines, thioxopropanoic acid ethyl ester 7 and 4-oxothiazolidine benzene sulfonamides. All the newly synthesized compounds were executed for their in vitro anticancer activity against liver cancer cell line 65
(HEPG-2) in which hCAII is over expressed and exhibited promising activity as compared to doxorubicin. Among test compounds, compounds (185), (186), and (187) (IC50; 43, 43, 46 µM) exhibited most potent anticancer activity at 10, 25, 50, 100 µM than doxorubicin (IC50; 32 µM). This activity was remarkably increased upon further investigation in combination with radiation (IC 50; 30, 30, 32 µM) [209]. Ramla et al. reported synthesis of 2-(1-benzyl-2-methyl-1H-benzimidazol-5-ylimino)-3(substituted)-thiazolidin-4-one
and
3-(2-methyl-1H-benzimidazol-5-yl)-2-substituted-
thiazolidin-4-one derivatives in order to find out their inhibitory activity against EBV-EA induction. Results of antitumour activities indicated that compound (188) having the thiazolidinone ring linked to the 5th position of the benzimidazole through imino nitrogen was found to be most effective in the series. Compound (188) was found to be more active than the non-cyclized thiourea derivatives having a benzyl or p-methoxyphenyl as substituents. However the cyclized compounds having alkyl or phenyl groups as substituents to thiazolidinone derivatives (other than compound 188) were least active [210]. Gududuru et al. reported synthesis of 2-aryl-4-oxo-thiazolidin-3-yl-amides and evaluated for their in vitro antiproliferative activity against five human prostate cancer cell lines namely DU-145, PC-3, LNCaP, PPC-1, and TSU, and in RH7777 cells (negative controls). Among the test compounds, compound (189) was identified as most potent compound as compared to 5-FU against RH7777 (IC50; 11.5 µM), DU-145 (IC50; 11.2 µM), PC- 3 (IC50; 6.5 µM), LNCaP (IC50; 7.9 µM), PPC-1 (IC50; 5.4 µM) and TSU (IC50; 6.4 µM), respectively with 2–5 fold lower selectivity compared to RH7777 cell line [211]. Tzanova et al. introduced novel synthetic benzophenone analogues and evaluated for their in vitro antioxidant activity against cancerous MCF-7 and the non-cancerous hTERT-HME1 mammary cells, and the H9c2 cardiomyoblastic cell lines. Compound (190) (IC20; 93.5 ± 6.8, 149.9 ± 4.3 µM for MCF-7, hTERT-HME1, respectively) displayed the significant antioxidant activity and low cytotoxicity below 100 µM. Compound (190) was found to be 1.5 times more potent than the reference antioxidant (a water soluble derivative of vitamin E) trolox (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid) at 100 µM [212]. A molecular docking-based screening of novel 2-(4-phenylthiazol-2-yl) isoindoline-1,3-dione derivatives against prostate cancer cell lines (PC-3 & LNCaP) was demonstrated by Saravanan et al. The compound (191b) bearing flouro group exhibited potent activity on 66
LNCaP (IC50; 5.96 ± 1.6 µM), and moderate activity against PC-3 cell lines as compared to standard drug bicalutamide. While the compounds, (191a) & (191c) were moderately active against the LNCaP cell line. It is evident that the substitution at position R1 with the groups OCH3, CN and NO2 were influenced by the better activities compared to other groups. Thus, it can be concluded that 4-substituted phenyl-1,3-thiazole core showed the greater anticancer activities compared to aromatic substitution on 1,3-thiazole at 5th position [213]. Novel thiazoloquinazoline derivatives were developed by Ghorab et al. in order to screen its biological potential against cytoprotective enzyme NAD(P)H: Quinone oxidoreductase in Hepa1c1c7 murine hepatoma cells. The thiazoloquinazoline (192) exhibited remarkable activity with 1.34 fold NQO1 inducer activity. It was worth mentioning here that incorporation of thiazole moiety within a heterocyclic ring system (quinazoline) increases the NQO1inducer potency. Rest of the synthesized compounds revealed weak NQO1inducer activity [214]. In an another study, Rahman et al. have synthesized three thiazole substituted coumarin derivatives and described their in vitro cytotoxicity study against Human Periodontal Ligament Fibroblast (HPDLF) cells using MTT assay. The cytotoxicity study revealed that coumarin derivatives containing the hydrazinyl thiazolyl group (193) exhibited less toxicity with a concentration of 5.51 µM to the inhibition concentration at 50% cell death (IC50) comparable to parent compound [215].
67
HO
O
S
O
O
N
HO
NH2
O
S
O
N
O
O
OH NH2
S
N
NH2
O (176)
(177)
O H N
N
(178) O
R2
O S
X N
R Active compound 179b; R; OCH3, X; S IC50; 0.026nM
Compd.
X
R
179a; 179b; 179c; 179d;
O S O S
OCH3 OCH3 Cl NO2
N
H N
N N O
CH3
N NH
N
N N
S
H3C S H3C
(183) NH S
O
H N
HN H
(185)
N
N
NH2
S
S
N
CH3 N
N
R
184a; 184b; 184c;
R H Cl OCH3
O
CH3
N
O
CH3
Active compound 184c; R; OCH3 IC50; 0.50 µM
O S NH2 O
H N
O H2N S O
(186) O
O
N
(184)
O S O NH2
N
R2 CF3 2,6-Cl2
Compd.
S N
R1 CF3 CH3
N
N
N
S
N H
N
O
CH3 Cl
N
CF3
(182)
CH3 N
Br
N
O
(181) O
N HN
H3C
H3C
O
H N
S
Compd. 180a; 180b; H3C
N
N
R1
N
(180)
(179)
S
O
N H HN
O S
N
N
S
(187)
O N H
C18H37
O2N
N S
(188)
(189)
Figure 33: Thiazole derivatives as cytotoxic agents (176-189). Recently, sixteen novel derivatives of 1-[(1R)-1-(6-fluoro-1,3-benzothiazol-2-yl)ethyl]-3alkyl carbamate were designed by Pejchal et al. In addition to their acetylcholinesterase
68
(AChE) and butyrylcholinesterase (BChE) inhibitor activity, compounds were also screened for their cytotoxic activity against SK-BR-3 cell lines. Among the tested four compounds (194a-194d), only (194b) at concentrations of 100 µM and 250 µM and (194d) at concentration 250 µM significantly (p ≤ 0.01) decrease viability with moderate selectivity in cell lines used. However, all the test compounds were able to produce low toxicity at 1-250 µM concentration range [216]. Grozav et al. scrutinized sixteen hydrazinyl-thiazolo arene ruthenium complexes and tested in vitro for their antiproliferative activity on cell lines namely HeLa, A2780, A2780 cis R along with a noncancerous cell line (HFL-1). All the complexes exhibited significant antiproliferative activity against three cell lines when compared with cisplatin and oxaliplatin. The complexes (195a) and (195b) were found to possess a significant reduction of cytotoxicity on the normal fibroblasts cell line HFL-1, with (IC50; 181 µM) and (IC50; 36.6 µM), respectively. Moreover the cytotoxicity of these complexes on HeLa cells was found very low (>100 µM), which clearly indicated that hydrazinyl-thiazole compounds have beneficial effect of complexation with arene ruthenium units [217]. Laczkowski et al. introduced ten thiazole-based nitrogen mustards and screened them against human cancer cells lines (MV4-11, A549, MCF-7 and HCT116) and normal mouse fibroblast (BALB/3T3). Antiproliferative activity data revealed that compounds have varied degree of activity against the cancer cell lines. Compound (196a) has shown most potent activity against human leukemia MV4-11, MCF-7, HCT116 and BALB/3T3 cells with IC50 values of 2.17 µg/ml, 3.42 µg/ml, 3.02 µg/ml, 3.2 µg/ml, respectively than the standard drug cis-platin. However one compound (196b) was also found potent against MCF-7 cells with IC50 values of 3.02 µg/ml as compared to the cis-platin (IC50; 2.46 µg/ml). From the SAR viewpoint, substituents
(NHSO2CF3)
(196b)
and
(NHSO2C6F5)
(196a)
imparts
the
strong
antiproliferative activity in almost all tested cancer cell lines MV4- 11, A549, MCF-7 and HCT116 [218]. Wu et al. contributed a novel series of 5-(benzo[d][1,3]dioxol-5-ylmethyl)-4-(tert-butyl)-Narylthiazol-2-amines and tested for their antitumour activities against HeLa, A549 and MCF7 cell lines. Generally, the test compounds showed promising anticancer activity against all the cell lines below 5 µM. Compound (197a) exhibited potent activities against HeLa and A549 cell lines with IC50 values of 2.07 ± 0.88 µM and 3.52 ± 0.49 µM, respectively. Compound (197b) (IC50; 2.06 ± 0.09 µM) was the most active compound against A549 cell 69
line, while compound (197c) (IC50; 2.55 ± 0.34 µM) showed the best inhibitory activity against the MCF-7 cell line [219]. O
R1
H N
HO
O N
O S
OH
N
Active compound 191b; R1; CN, R2; F IC50; 5.96 µM
R2
S O
(190) (191)
Compd.
O
H3C
O
N S
O HN N
N
(192)
191a; 191b; 191c;
O
N
+ O Cl
R Compd.
HN O
194a; 194b; 194c; 194c;
S (194)
R
H
OCH3 OCH2CH3 OCH2CF2Cl OCH2CF2CHF2
R O S O HN
N
S N
N H (196)
196a; 196b;
R 2,3,4,5,6-F5 4-CF3
Ru N
S
N H
CH3
(195)
Compd. 195a; 195b;
Cl
Cl-
O
N
R
Cl
Compd.
OCH3 F CN F NO2 F
H3C
N
R2
O
S
(193)
F
R1
R 2,4-Cl2 2-Cl
N H3C Compd. 197a; 197b; 197c;
H3C
R 3,5-(CF3)2 3-Cl 4-NO2
CH3 O
N R
S O
NH (197)
Figure 34: Thiazole derivatives as cytotoxic agents (190-197). Balanean et al. have introduced novel N’-2-(2-methylamino)thiazol-4-yl)acetohydrazidehydrazone derivatives and performed their antiproliferative activity against the cell lines namely Hs578T, HeLa and HEPG2. Among the test compounds, compound (198) having substitution of 3-formylchromone in C-6 position was proved to be most potent with IC50 values of 0.823 µM, 5.077 µM, 4.950 µM corresponding to HeLa, HEPG2 and Hs578T cells, respectively [220]. A new series of series of N-{(1-(4-(4-bromophenyl)thiazol-2-yl)-3-substituted-phenyl-1Hpyrazol-4-yl)methylene}-1H-1, 2, 4-triazol-3-amines were synthesized and screened for their 70
antiinfective and cytotoxic activities by Bansal et al. Out of the test compounds, compound (199) bearing a p-NO2-phenyl have been emerged as most potent by exhibiting cytotoxic activity GI50 value of 1.2 µg/ml against HeLa cell lines as compared to adriamycin (GI50, <10 µg/ml). On the other hand, GI50 value were observed >80 µg/ml against the human breast cancer cell lines (MCF-7) [221]. Anticancer activity of benzimidazole-thiazolidinedione derivatives against human cancer cell lines of prostate (PC-3 and DU-145), breast (MDA-MB-231), lung (A549) and a normal breast epithelial cells (MCF10A) were executed by Sharma et al. Biological data indicated that A549 lung cancer cell line was most susceptible towards the test compounds. Among the test compounds, compound (200) exhibited encouraging cytotoxicity with IC50 value of 11.46 ± 1.46 µM on A549 lung cancer cell line as compared to the standard 5-FU (IC50 value of 30.47 ± 1.90 µM). It was also found that treatment of compound (200) on A549 lung cancer cell led to G2/M phase of cell cycle arrest and able to induce apoptosis [222]. Tay et al. developed novel 4-naphthyl-2-aminothiazole-containing compounds and screened them for their in vitro antimicrobial and anticancer activities. Some of the compounds showed remarkable antibacterial and antifungal activities. Anticancer and cytotoxic activities were carried out against human hepatocellular carcinoma Hep-G2 and human lung adenocarcinoma A549 cell lines while doxorubicin was used as reference drug with IC50 values 5 µM and 0.5 µM. Compounds (201a) and (201b) were determined as the most cytotoxic and anticancer potential compounds. Compound (201a) showed 66% cell viability IC50 values 200 µM for an incubation period of 24 h against Hep-G2 cell lines. Whereas, against adenocarcinoma cell lines (A549), only compound (201c) with 57% viability at 200 µM for 48 h was found as most potent anticancer agent [223]. A novel series of thiazoles bearing 1,3,4-thiadiazole scaffold was executed by Gomha et al. in order to screen for their in vitro anticancer activity against liver HEPG2 cancer cell line. Out of the test compounds, the compound (202) having ester group (CO2Et) at position 2 of the thiadiazole ring have shown superior antitumour activity (IC50; 0.82 µM) against liver carcinoma cell line (HEPG2) in comparison to the standard drug doxorubicin (IC50; 0.72 µM). However, some other compounds had also shown good antitumour activity against HEPG2. The SAR study revealed that presence of electron-withdrawing group at the position 2 and 4 in the aryl moiety enhances the activity and electron-donating groups such as methyl
71
or methoxy at the position 4 in the aryl moiety of the thiadiazole ring attributed to decrease in the cytotoxic activity [224]. Park et al. have screened 18 new imidazo[2,1-b]thiazole-containing compounds for their in vitro antiproliferative activities against A375P human melanoma cell line and NCI-60 cell line panel. Some of the test compounds exhibited superior activity against the cell lines used than the standard drug sorafenib. Out of test compounds, compounds (203a) and (203b) demonstrated higher potencies against A375P human melanoma cell line than sorafenib (IC50; 5.6 µM) with sub-micromolar IC50 values of 1.40 and 0.79 µM. Compounds (203a) and (203b) demonstrated high selectivity ratios of 4.25 and 4.14 against melanoma as compared to other cancer types. In silico ADME profiling results together with in vitro antiproliferative activities make compounds (203a) and (203b) promising leads for development of selective and potent agents for treatment of melanoma [225]. In an another study, Park et al. developed a new series of pyrimidinyl-imidazo[2,1-b]thiazolecontaining compounds and investigated their antiproliferative activity against A375 human melanoma cell line. Biological data revealed that all the compounds exhibited moderate antiproliferative activity against the cell line as compared to the standard drug sorafenib. Among the test compounds, the cyclic sulphonamide derivative (204) (IC50; 1.9 µM) demonstrated most potent antiproliferative activity as compared to sorafenib (IC50; 5.6 µM) [226]. Two series of novel 2-substituted 5,7-dihydroxyanthra[2,1-d]thiazol-6,11-diones of natural rhein were inspected by Liang et al. for their in vitro antitumour activities against A549 and HeLa human cancer cell lines. Some compounds were found to be more potent than rhein. Out of the test compounds, compound (205) bearing methyl piperazine moiety giving the IC50 of 5.4 µM and 4.3 µM, respectively, and was around 30 times more potent than rhein (IC50 115.1 µM & 123.2 µM, respectively) [227].
72
O
H N
O
N
N
HN H3C
NO2
CH3
Br
O
N
N
S
N
S
(198)
N
N
(199)
H3C N
S N
N
O
N NH O HN
O
N S
O
(200)
N
CH3
S
H N
O CH3
S N
N
N
O Compd. 201a;
N
R
(202)
N
Cl
S 202b;
(201)
N
F O
H2C 202c; S
Cl
R
HN N
S
O N
CH3
NH N
N N
N NH
N
N
R
HN OH
203a; 203b;
R H 2-OH
S
HO
N
S
(204)
N
O (203)
Compd.
HO
O
N
N
N CH3
O (205)
Figure 35: Thiazole derivatives as cytotoxic agents (198-205). In a study, Santos et al. reported 6,7-bis(hydroxymethyl)-1H,3H-pyrrolo[1,2-c]thiazoles for their anticancer activity targeting triple-negative breast cancer (MCF-7, HCC1954 and HCC1806 cell lines). Among all the test compounds, compounds (206) and (207a) was the most promising anti-proliferative agent against HCC1954 cancer cell lines with IC50 values of 0.3 µM and 0.6 µM, respectively. Against HCC1806 cell line, (207b) is the most promising compound with IC50 value of 5.4 µM. The SAR study revealed that presence of a hydroxyl phenyl group at C-3 seems to improve the anti-cancer activity for the TN cell line [228]. A series of novel p-toluenesulfonyl-hydrazinothiazoles and hydrazino-bis-thiazoles was prepared and screened for in vitro anticancer activity by Zaharia et al. Some of the 73
compounds were found to possess good anticancer activity against prostate DU-145 and hepatocarcinoma Hep-G2 cancer cell lines than the standard drug doxorubicin. Compounds (208a) (IC50; <5.65 µM on Hep-G2) and (208b) (IC50 of 4.68 µM on DU-145 and below 4.51 µM on Hep-G2) showed the best anticancer activities [229]. Shao et al. introduced novel ferrocenyl-containing thiazole-containing compounds and scrutinized them for their anticancer activity against three human cancer cell lines including HL-60 leukaemia, BGC-823 gastric carcinoma cells and Hep-2 laryngic carcinoma cells. Some compounds exhibited good anticancer activity at concentration of 10 µM. Ccompound (209) having methoxy substitution displayed most potent cytotoxic activities on HL-60 leukaemia, BGC-823 gastric carcinoma cells and Hep-2 laryngic carcinoma cells with 81.40, 63.41, and 53.11% inhibition, respectively at 10 µM [230]. Synthesis and anticancer activity of novel 2,6-disubstituted benzothiazole-containing compounds against three human cancer cell lines MCF-7, HeLa and MG63 have been accomplished by Sadhasivam et al. Out of the test compounds, sulfonamide derivative (210) demonstrated most potent cytotoxicity against MCF-7, HeLa and MG63 with IC50 values of 36, 44 and 34 µM, respectively in comparison to cisplatin (IC50; 3.5 µM). On the other hand, compound (211) also displayed cytotoxicity with IC50 range of 48 to 53 µM against all the cell lines [231]. Cytotoxic activity of new thiazolyl-pyrazoline derivatives against A549 human lung adenocarcinoma and NIH/3T3 mouse embryonic fibroblast cells was reported by Altintop et al. Among the test compounds, compound 2-[5-(4-fluorophenyl)-3-(5-chlorothiophen-2-yl)4,5-dihydro-1H-pyrazol-1-yl]-4-(4-bromophenyl)thiazole (212) was identified as most favourable anticancer agent against A549 cancer cells with an IC50 value of 62.5 µg/mL when compared with cisplatin (IC50; 45.88 µg/ml) and non-toxic potential against NIH/3T3 cells [232]. Several substituted 4-aryloxy- and 4-arylsulfanyl-phenyl-2-aminothiazoles were screened for their cytotoxicity activity against estrogen-positive, estrogen-negative, and adriamycinresistant human breast cancer cell lines by Gorczynski et al. Compounds (213a) & (213c) showed selectivity against T-47D (IC50; 0.917 & 0.54 µM, respectively), compound (213b) against MDA-MB-435 (IC50; 0.759 µM) were emerged as most potent cytotoxic compounds endowed with excellent inhibitory activities. From SAR viewpoint, it was found that electron 74
donating para-methyl substituent in compound (213c) showed increased efficacy over the electron-withdrawing para-chloro thiazole in compound (213a) [233]. Andreani et al. described synthesis and antitumour activity of 6-substituted imidazothiazole guanylhydrazones. All the compounds were subjected for their antitumour activity against NCI cell lines. Almost all the cell lines were found to be more sensitive towards 2-methylimidazothiazoles for which the antitumour activity was higher (214-216) with mean pGI50 values of 5.03-5.40 µM displaying lowest toxicity. Compound (217) was effective on growth and death of HL-60 leukaemia Cells (selectivity towards leukaemia Cells), induces apoptosis as well as causes mitochondrial disruption of ∆Ψm parameter [234]. In an another study, Andreani et al. reported new guanylhydrazones analogues of Imidazo[2,1-b]thiazoles for their antitumour activity at NCI cell lines. Among them, guanylhydrazone
of
2-chloro-6-(2,5-dimethoxy-4-nitrophenyl)imidazo[2,1-b]-thiazole-5-
carbaldehyde (218) have been emerged as most active compound exhibiting log GI50 values (panel/cell line): -5.81 (colon/COLO 205), -6.23 (ovarian/OVCAR-3), -5.84 (renal/RXF 393), and -5.72 (leukemia/K-562). Moreover the compound (218) was found to be an inhibitor of complex III of the mitochondrial respiratory chain and is able to induce apoptosis in the cell lines HT29 and HL60 [235]. Popsavin et al. synthesized two novel tiazofurin analogues starting from D-glucose and tested for their in-vitro antiproliferative activity. Analogues (219a) and (219b) exhibited potent cytotoxic activity against some human leukaemia and solid tumour cell lines, but none of them found to exhibit any significant cytotoxicity towards normal foetal lung MRC-5 cells. Remarkably, compound (219a) was found to be 570-fold more potent than tiazofurin against MCF-7 cells. Consequently, same analogue was also active against HeLa cells, but it was almost 2-fold less potent with respect to the parent molecule 33 while compound (219b) showed most powerful cytotoxicity against HL-60 and HeLa cells being almost 100-fold more active than tiazofurin [236].
75
HO
CH3
HO
HO
CH3
HO
N S
R
207a; 207b;
H OH
S
(206)
N
(207)
O S NH O HN
H3C
OH
N
Compd.
N
Compd.
S
R
H N
Fe
R
208a; 208b;
O
H COOCH2CH3
(209) H N
NH N
HN O (211)
F
O
S
+
N
H3N I-
Compd.
R
N
(213)
(212)
HN
NH N
H3C
N S
N
N S
N
H3C
S (215)
(214)
N
HN N HN N
NH
H3C
O CH3
O CH3
N
N
HN
H3C
CH3
S
H N
4-Cl 3,4-Cl2 4-CH3
O2N
S
H3C H H2N N
R
213a; 213b; 213c;
S
Br
S
NH2
CH3
N H
S
CH3 O
N N
O
N
(210)
Cl
OCH3
N HN
S
S O
N S
CH3
(208) O
N
S
NH N
H3C N
N
H3C S
(216)
N
N H
(217)
H2N HN
NH N N
Cl
S
CH3 O
HO
O N (218)
O
NO2 CH3
S N
HO
O
NHCOR NH2
Compd.
R
219a; 219b;
C6H11 C11H23
(219)
Figure 36: Thiazole derivatives as cytotoxic agents (206-219). A novel series of 1, 3-thiazole-benzofuran and 1, 3-thiazole-pyrazole-benzofuran derivatives was synthesized by Gomha et al. Some of the newly synthesized derivatives were tested for their in vitro cytotoxic activity against the human breast carcinoma (MCF-7) cell lines and compared with doxorubicin. Compound 4-Methyl-5-(p-tolyldiazenyl)-2-(2-(1-(4, 6, 7-
76
trimethoxybenzofuran-5-yl) ethylidene) hydrazinyl) thiazole (220) appeared to be a potent cytotoxic agent (IC50; 0.69 µM). From SAR viewpoint, introduction of electron-donating group (methyl) at C4 of the phenyl group at position 5 in the 1, 3-thiazole ring improves the antitumour activity [237]. A new facile synthesis of heterocycles containing thiazole and 1, 3, 4-thiadiazole or two thiazole rings was introduced by Gomha et al. These compounds were subjected for their in vitro anticancer activity against hepatocellular carcinoma cell line (HepG-2). Among the test compounds, the best results were obtained in compounds (221) (IC50; 1.61 ± 1.92 µg/ml) and (222) (IC50; 1.98 ± 1.22 µg/ml). SAR study concluded that thiazole ring and 4-CH3-Ph are essential for anticancer activity in most potent compound (221). Furthermore, presence of the N-phenylcarboxamide group in compound (222) also enhances the activity [238]. Dos Santos Silva et al. have synthesized hybrids of pyridyl and 1,3-thiazole moieties and screened against HL-60 (leukemia), MCF-7 (breast adenocarcinoma), HEPG2 (hepatocellular carcinoma), NCI-H292 (lung carcinoma) human tumour cell lines and non-tumour cells (PBMC, human peripheral blood mononuclear cells). Among all the test compounds, compound (223a) and compound (223b) presented cytotoxic activity and most favourable selectivity index in all tumour cell lines, including HEPG2 (IC50; 2.2 and 5.6 µM, respectively). Further, these compounds produced their cytotoxic effect without causing toxicity to normal cells (PBMC) (IC50 > 30 µM) with a most favorable selectivity index [239]. Cytotoxic activity of a series of new quinoline-thiazole based azo compounds against MCF-7 (human breast cancer cell line) and K562 (CML cell line) was reported by Sarangi et al. The results of in vitro cytotoxic activity of the synthesized compounds has revealed that the compound 4-(((Z)-(2-chloroquinolin-3-yl) (4-phenylthiazol-2-ylimino) methyl) diazenyl)benzenesulfonic acid (224) showed excellent cytotoxic action against MCF-7 & K562 cancer cell lines (IC50; 15.96 & 13.05 µM, respectively) [240]. Since androgen receptor (AR) plays a stimulator role in many different prostate cancer cell types during cancer, targeting androgen receptor -DNA-binding domain (AR-DBD) some novel thiazole-based derivatives were introduced by Xu et al. Among the test compounds, only compound (225) containing a methylketone moiety have shown inhibitory effect on human prostate cancer cell line LNCaP/AR with IC50 value of 0.38 µM without significant antiproliferative effects on other cell lines PC-3 (AR-negative), SW620, MCF-7 (ER77
positive), and L-O2 (non-cancerous). SAR study revealed that reducing the methylketone in (225) to alcohol significantly reduced the activity [241]. Some new thiazole, pyridinone, thiophene, chromene and pyrazole derivatives containing biologically active acetanilide nucleus were synthesized by Abdel-Latif et al. In vitro cytotoxic activity of the synthesized heterocyclic scaffolds was assessed against human breast cancer cell line (MCF-7) and compared with 5-fluorouracil. Among all the screened thiazolecontaining compounds, compounds (226) & (227) exhibited significant cytotoxic activity (IC50; 6.9 & 9.3 µg/ml, respectively) as compared to 5-fluorouracil (IC50; 5.5 µg/ml) [242]. Some novel thiophene, thiazole and coumarin based on benzimidazole derivatives were developed by Mohareb et al. and screened for their in vitro their cytotoxicity and toxicity. Cytotoxic activity was carried out against human lung carcinoma (A549), lung cancer (H460), human colorectal (HT29), gastric cancer cell (MKN-45), glioma cell line (U87MG) and cellosaurus cell line (SMMC-7721) using foretinib as standard reference. Among the tested thiazole-containing compounds, derivatives (228a) (IC50; 0.25-3.28 µM) & (228b) (IC50; 0.23-0.82 µM). Whereas, compound (228b) was found to possess non-toxicity against shrimp larvae indicated that compound may provide a suitable lead molecule in cancer treatment [243]. A new series of thiazole, thiadiazole and oxadiazole based1,4-dihydropyridine derivatives was synthesized by Ahmed et al. In vitro cytotoxic activity of newly synthesized compounds was preformed against liver (HEPG2), cervical (HeLa), and breast (MCF-7) cancer cell lines, while doxorubicin was used as standard. Among the tested thiazole compounds, compounds (229a) and (229b) exhibited highest toxicity against cervical (HeLa) and breast (MCF-7) cancer cell lines (IC50; 2 nM & 3 nM, respectively) as compared to doxorubicin (IC50; 5 nM & 2 nM, respectively). SAR studies revealed that both (229a) and (229b) compounds with electron withdrawing groups 4-Cl-Ph exhibited significantly higher activity than those of compounds containing an electron withdrawing group 4-NO2-Ph [244]. In vitro antitumour activity of a new series of 1,4-bis(1-(5-(aryldiazenyl)thiazol-2-yl)-5(thiophen-2-yl)-4,5-dihydro-1Hpyrazol-3-yl)benzene derivatives was performed by Gomha et al. Anticancer activity was done against hepatocellular carcinoma (HEPG2) cell line, using doxorubicin as a reference drug (IC50; 0.72 ± 0.18). The results revealed that compound (230) exhibited most potent anticancer activity (IC50; 1.37 ± 0.15) against hepatocellular carcinoma (HEPG2) cell line than the standard drug. From SAR study revealed that substituent at 78
position 4 in the thiazole ring and introduction of a thienyl ring in compound (230) affect the in vitro anticancer activity, while electron-withdrawing group follows the order of activity as; nitro > chlorine > bromine at the para position of the phenyl group attached to thiazole ring enhances the antitumour activity [245]. Two series of 2-aminothiazole and isoquinoline fused naphthalimide derivatives were prepared and screened for their anticancer activity against hepatocellular carcinoma by Ge et al. Among the tested thiazole fused naphthalimide derivatives, derivative (231a) exhibited maximum potency against hepatocellular carcinoma (SMMC-7721, HEPG2, HCT-116, and K562) with IC50; 1.61± 0.13, 4.67± 0.31, 3.81± 0.25, and 12.41± 1.56, respectively. Further, compound (231a) caused acute toxicity in tumour transplant models: solid tumour (tumour growth inhibition evaluation) and pulmonary metastasis tumour (tumour metastasis evaluation) against mice hepatoma cell line. However, compound (231b) exerted potent effects against these models with no toxicity. Compound (231b) exerted maximum inhibition against cancerous liver cell growth mainly by G2/M phase arrest by the up-regulation of cyclin B1, CDK1 and p21 [246]. Antibacterial and cytotoxic activities of 2-(3’-Indolyl)-N-arylthiazole-4-carboxamide derivatives were described by Tanak et al. In vitro cytotoxicity was done against a panel human cancer cell lines using doxorubicin as standard (IC50; 0.45-7.65 µM). Among the tested thiazole carboxamide derivatives, derivative (232a) (IC50; 8.64 µM against HEK293T) and (232b) (IC50; 3.41 µM against HeLa) were identified as the most potent compounds as compared to the standard drug. The preliminary mechanism of action studies indicated that thiazole carboxamide (232a) was crucial for selectivity and cytotoxicity against HeLa cells via induction of cell death by apoptosis [247].
79
CH3 O N NH S O N CH3 O
N
H3C
N H3C
CH3
CH3
N N
N HN
H3C O HN CH3
N
O
S
S
O
N
CH3
N
(220) (221)
O NH N
S
O S
N
N
N H
N
H N
N
N
(222) Cl
N
N N
O OH S O
N H
(225) H N
S
N
N H
CH3
N O R
NO2
CH3
S
NH N
H3C
NH O
(228)
CH3 OCH2CH3
NH
S
N
N
N
N
S R (229)
229a; 229b;
N
228a; 228b;
H3C
Compd.
N
Compd.
(227)
(226)
O
N CH3
N
R
S
S N
O
CH3
O
O O
CH3 H
O
N
O
NH
N
N
H3C
N
R
223a; 223b;
S
O
N
CH3
Compd.
(223)
S
(224)
Cl
S
CH3
S N N
R Cl NO2 O2N
N N S
N
N
N
CH3 S (230)
Figure 37: Thiazole derivatives as cytotoxic agents (220-230). Synthesis of a new series of coumarin substituted thiazolyl-3-aryl-pyrazole-4-carbaldehydes and in vitro cytotoxic activity against MCF-7, DU-145 and HeLa cell lines was reported by Vaarla et al. Out of the test compounds, compounds (233a) against HeLa (IC50; 5.75 µM) and (233b) against HeLa cells and DU-145 cell (IC50; 6.25 µM, 10.81 µM, respectively) 80
exhibited significant cytotoxic activity as compared to the standard drug doxorubicin (IC50; 2.49-3.92 µM). Hence, it can be concluded that presence of pharmacologically active moieties like coumarin, thiazole and pyrazole along with a potential functional group like aldehyde in their structures does contributes to potential cytotoxic activities [248].
R
H N
O
CH3 O
H N
S O
N
O
.nHCl
H3C
N
O
S
O H3C
N H
NH2
CH3
O
N (232) (231) Compd. Compd. 231a; 231b;
R
R1
R2
n
CH2CH2NH2 H
232a; 232b;
4 3
OCH3 F
3,4,5-(OCH3)3 4-OCH3
CH3 O
O
Compd.
R N
N N
O
233a; 233b;
R 6,8-Cl2 6,8-Br2
S (233)
Figure 38: Thiazole derivatives as cytotoxic agents (231-233). 3
An insight view of recent patents filed on thiazole-containing compounds as anticancer agents The main objectives of this section is to deals with the patents filed on thiazole-containing compounds reported in international patents from all companies (Given under the section 3.1; Table 2). Thiazole is a well-known and important sulphur and nitrogen containing fivemembered heterocyclic compound. Thiazole occurs in nature and numbers of scientist have carefully revised various methods for synthesis of thiazole [249]. In past two decades, a lot of derivatives containing thiazole ring system have been developed to find a new drug that works in plethora of cancer with fewer side effects. The present review gives an account of the recent therapeutic patent filed on applications of selected thiazole-containing compounds working in cancer treatment. Findings revealed that, a vast variety of patents have been
81
registered in last two decades on thiazole-containing compounds which has drawn their utmost attention due to target specific anticancer activity. Thus, thiazoles have found their prominent role in order to develop more effective and clinically interesting anticancer agents.
3.1
Table 2 List of some patents related to anticancer activity of thiazole [250-278]. S.No. 1.
Date Nov 25, 2015
Patent no. CN105078977 A
Invention disclosed Application of 5-(2-nitro ethyl) thiazole derivatives as anticancer drug.
Ref. [250]
2.
Oct 1,2015
US20150274714 A1
[251]
3.
Feb 5, 2015
WO2015016442 A1
4.
Mar. 25, 2014
US 8680103 B2
Anti-invasion, anti-migration and thiazole analogs for treatment of cellular proliferative disease. Novel phenylthiazole-based hydroxamic acid and anti-cancer composition containing active ingredient. Preparation of 2-aminothiazole-5-aromatic carboxamides as kinase inhibitors.
5.
Aug. 5, 2014
US 8796298 B2
[254]
6.
Jul 22, 2014
US8785444 B2
Combination of a B-Raf inhibitor: N-{3-[5(2-amino-4-pyrimidinyl)-2-(1,1-dimethyl ethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}2,6difluorobenzene sulfonamide and the Akt inhibitor: N-{(1s)-2-amino-1-[(3fluorophenyl)methyl]ethyl}-5-chioro-4-(4chioro-1-methyl-1H-pyrazol-5-yl)-2-10 thiophenecarboxamide useful in the treatment of cancer. Thiazoles and pyrazoles valuable as kinase inhibitors.
7.
Jul. 18, 2013
US 2013/0184280 Substituted thiazole derivatives as VEGFR2 A1 kinase inhibitors.
[256]
8.
Dec. 19, 2013
[257]
9.
Mar. 12, 2013
US 2013/0338201 A method of cancer management with 2-(1HA1 indole-3-carbonyl)-thiazole-4 carboxylic acid methyl ester. US 8394960 B2 Thiazole carboxamide derivatives and their use to treat cancer.
10.
Mar. 26, 2013
US 8404691 B2
[259]
11.
Feb. 21,2012
US 8119812 B2
Imidazothiazole derivatives having a proline ring structure having anti-tumor activity by inhibition of murine double minute 2 (Mdm2) or their salt. The novel invention inhibited the CDC7 protein kinase activity, and control of cell proliferation.
[252]
[253]
[255]
[258]
[260]
82
12.
Apr. 12, 2012
US 2012/0088759 Thiazole derivatives as orexin receptor A1 antagonists.
[261]
13.
28.Aug. 2012
US8252822 B2
[262]
14.
Sep. 18, 2012.
US 8268811 B2
Imidazothiazole-chalcone derivatives as potential heterocyclic compounds and their anticancer agents. Thiazoles and pyrazoles useful as kinase inhibitors.
15.
Aug. 04,2011 Mar. 10, 2011 Jun. 15, 2010 Feb 16,2010
US 2010190299 A1 US 2011/0060013 A1 US 7737134 B2
[264]
Feb. 17, 2009 Oct 23,2008
US 7491725 B2
Feb. 5, 2008 Feb. 15,2007
US 7326727 B2
23.
Oct. 2, 2007
US 7276602 B2
Novel thiazole derivatives having a CDC7 inhibitory action. Thiazoles and pyrazoles useful as kinase inhibitors. Thiazole derivatives as anticancer agents and their use. Selective anti-cancer agents; Thiazolidinones amides, thiazolidine carboxylic acidamides, and serine amides including polyamine conjugates Development of 2-aminothiazole-5-aromatic carboxamides as kinase inhibitors. Use of compounds for the preparation of pharmaceutical compositions for the treatment of pathologies in which inhibition of the interaction between HIF-1α and p300 is beneficial, in particular as antiangiogenic medicaments for the therapy of solid tumors. Novel furanthiazole derivatives which are useful as inhibitors of heparanase. Thiazole derivatives and their production and uses as pharmaceutical agents as inhibitors of polo kinases in cancer, auto-immune diseases, cardiovascular diseases. Novel isothiazole derivatives that is useful in the treatment of hyperproliferative diseases.
24.
Apr 13,2006
US 0079503 A1
25.
Jan. 20, 2005.
26.
Mar. 16, 2004
US 6706718 B2
Novel 3-(2,4 dimethylthiazol-5-yl)indeno[1,2- [275] c]pyrazol-4-one derivatives which are useful as cyclin dependent kinase (Cdk)inhibitors.
27.
Apr. 10, 2001
US 6214851 B1
N-Adamant-1-yl-N1-[4-chlorobenzothiazol-2- [276] y1] urea useful in the treatment of inflammation and as an anticancer radiosensitizing agent.
16. 17. 18.
19. 20.
21. 22.
US 7662842 B2
US 20080261980 A1
US0037862 A1
Thiazoles and their production and uses as pharmaceutical agents as inhibitors of polo kinases in cancer, auto-immune diseases, cardiovascular diseases. US 2005/0014767 Benzimidazole, benzoxazole,and A1 benzothiazole derivatives for the treatment of cancer and other diseases.
[263]
[265] [266] [267]
[268] [269]
[270] [271]
[272] [273]
[274]
83
4
28.
Apr 26, 2016
US9321777 B2
6-Triazolopyridazine sulfanyl benzothiazole derivatives as met inhibitors.
[277]
29.
Feb-112016
US 20160038472 A1
Agent for the prophylaxis and/or treatment of neoplastic diseases.
[278]
Novel thiazole-containing cyclic peptides as anticancer agents Peptide-based chemotherapies are currently being used to treat cancer. These cyclic peptides offers unique advantages such as low molecular weights, the ability to specifically target tumour cells, and low toxicity in normal tissues [279]. Current research emphasized on developing such peptide derivatives that can assist as cancer targeting moieties and permeabilize membranes with eventually cytotoxic impacts. Considerably, the challenge lies in the development of the clinical application of therapeutic peptides. Some properties like improved delivery to tumours, minimized non-specific toxic effects and discerning pharmacokinetic properties are highly warranted to produce a powerful therapeutic peptide for cancer treatment [280]. In this review, we will survey some thiazole based modified cyclic peptide antibiotic and their applications in cancer treatment.
4.1
Berninamycin Berninamycin is a highly modified cyclic peptide antibiotic produced by Streptomyces bernensis. It contains two oxazole rings together with a novel pyridothiazolopyridinium chromophore, ‘berninamycinic acid. Berninamycin is known to be a potent inhibitor of protein synthesis in Gram-positive bacteria and, in bacterial extracts, it inhibits the synthesis of polypeptides in response to homopolynucleotide ‘messengers’ or phage RNA [281].
84
O
H N
O
CH2 NH2
N H CH 2 N
O
O N
O
N
S
N H
O
O
NH NH
O
H3C
N O
H3C HN H3C O
HN N
CH2 O CH3
O HN
H3C O
O
HN H3C
OH
Figure 39: Berninamycin Isolation and identification of berninamycin A: The culture of S. atroolivaceus using ISP2 agar medium was extracted by acetone and the acetone extract was filtered and concentrated to aqueous residue by the rotary evaporator. The acetone extract was subjected to open column chromatography using hydrophobic resin eluted with 20% MeOH, 60% MeOH, and MeOH. Berninamycin A was isolated by repeatedly subjecting MeOH fraction to preparative HPLC. The identification of berninamycin A was accomplished by the combination of MS and NMR spectrum data. The High Resolution ESI-MS spectrum data determine the molecular formula C51H51N15O15S [282].
4.2
Micrococcin Micrococcin and micrococcin P are produced, respectively, by a bacterium related to Micrococcus varians and by Bucilluspumilis and it is now clear that these two antibiotics are identical. Micrococcin contains several thiazole rings. Micrococcin exert effects upon protein synthesis both in intact gram-positive bacteria and in prokaryotic cell extracts in general [283]. Micrococcin P1 is known to have powerful anticancer activity. Antibacterial activity of micrococcin P1 is attributed to inhibition of elongation factor G (EF-G) and initiation factor 2 (IF2) that prevent the binding of EF-G to the ribosome [282]. 85
CH3
O S
N H
N N
S
H N O H H3C
S
O
OH
S
N
O H3C
HO
S
HO
N
CH3 O
N
S
CH3 O
S
HN
HN
N NH H N
HO O
H3C
S H CH 3
H3C
CH3
HO
O
of
HN
H3C
as
anticancer
O
N
O
S
micrococcin
H N
O
N
S
N
NH
CH3
HN
CH3
S
Figure 41: Micrococcin P2
Figure 40: Micrococcin P1 Patent
O
N
N S
H N
N H
N
N
N
CH3
O
agents
and
method
for
diagnosing
cancer (WO2002102400 A1) A use of the macrocyclic peptide compound micrococcin as anticancer agents which exhibit selective toxicity against cancer cells. When the compounds micrococcin is treated to cancer cells and normal cells, they exhibit selective toxicity only against cancer cells to induce apoptosis of the cancer cells. The anticancer agent comprising at least one compound selected from the group consisting of the macrocyclic peptide compound micrococcin as an active ingredient, did not show toxicity against normal cells, but showed selective toxicity against cancer cells, thereby inducing selective apoptosis of cancer cells. Therefore, the macrocyclic peptide compounds micrococcin is useful as anticancer agents [284]. 4.3
Thiocillin I Thiocillins had been isolated from other strains of B. cereus, they had never been isolated from B. cereus ATCC 14579. To test whether B. cereus ATCC 14579 produces the thiocillins, assayed the extracts from its cell material and cell-free culture fluid by liquid chromatography (LC)/MS [285].
86
CH3
O S
S
H N H O H3C
N H
N N
OH
N N N
S
HO H
CH3 H O
S HN
O H3C HO
H
S
N
NH
H
HN
NH O
OH
HH3C O
N H3C
CH3
S
Figure 42: Thiocillin I Anticancer profile thiopeptides One of the biological properties of thiopeptides of major interest, apart from the antibacterial one, is anticancer activity. In this regard, thiostrepton was found to selectively kill cancer cells without showing any cytotoxicity against healthy tissues. Such a promising effect has been demonstrated to arise from selective inhibition of transcription factor forkhead box M1 (FOXM1). FOXM1 overexpression is associated with the development and progression of cancer and its selective targeting is a very large achievement, as transcription factors have been considered undruggable for a long time [286]. O
S
H3C NH
S
O
HO
NH NH CH3
O
N
H2N CH3
O
HN OH
O H N
N S
CH2
O
O
O
NH
CH3
O N
N O H3C HO
CH2
O S
HN NH
N
S O
H3C
N
N
H N
HO
CH2
NH O
H H3C H3C
87
Figure 43: Thiostrepton Patent on cancer therapeutic agent comprising thiopeptide with multiple thiazole rings (WO 2002066046 A1): This invention relates to cancer therapeutic agent comprising thiopeptide with multiple thiazole rings, its derivative or its pharmaceutically acceptable salt as an effective ingredient [287]. Since cancer cells show higher protein synthesis rate than that of normal cells, the protein synthesis inhibitor can show cancer therapeutic effects with selective toxicity against cancer cells. As for procaryotes, kanamycm, tetracyclme, chloramphenicol, erythromycin, streptomycin, lincomycm, clindamycin, thiostrepton and micrococcm are used as antibiotics inhibiting protein synthesis. Thiopeptide and its derivative of the present invention is preferably selected from a group consisting of compounds represented by formula 1 to formula 15, thiostrepton, micrococcin P, nosiheptide, siomycin, sporangiomycin, althiomycin, Promoinducin, Berninamycin, glycothiohexide alpha, Sch40832, GE37468A, GE37468B, GE37468C, GE2270, GE2270 factors C2a, GE2270 factors D2, GE2270 factors E, thiocillins, thiopeptin, amythiamicin A, sulfomycin, Thioxamycin and MJ3471F4A. Thiopeptide and its derivative of the present invention show useful effects as a cancer therapeutic agent by inducing apoptosis of cancer cells. Cancer therapeutic effect is confirmed by showing selective toxicity against cancer cells, when cancer cells and normal cells were treated with thiopeptide and its derivative of the present invention dissolved in a pharmaceutically acceptable solvent, such as dimethyl sulfoxide. Cancers, wherein thiopeptide and its derivative of the present invention can be applied, can be selected from a group consisting of gastric cancer, liver cancer, colon cancer, lung cancer, cervical cancer, breast cancer, ovarian cancer and leukemia. Particularly, thiopeptide and its derivative of the present invention can be effectively applied, but is not limited, to gastric cancer and liver cancer. In addition, it can be effectively applied to any known cancer. The IC50 value of thiopeptide and its derivative of the present invention against cancer cells range from 0.2 µmol to 12 µmol (Table 3). According to the present invention, a pharmaceutical composition containing thiopeptide with multiple thiazole rings and its derivative as an effective ingredient can be prepared by 88
mixing thiopeptide with multiple thiazole rings and its derivative with a pharmaceutically acceptable carrier [288]. 4.4
Table 3 Derivatives against various cancer cell line IC50; µM. Thiopeptide and
its Gastric cancer
derivatives
5
Liver Cancer
SNU- MKN-
SNU-
AGS
HEP
HEP 3B
638
74
216
Thiostrepton
0.30
4.2
0.41
0.4
0.71
0.82
0.74
Micrococcin P1
0.41
7.3
0.44
0.5
0.91
0.94
0.83
Siomycin A
0.91
6.21
0.75
0.71
1.3
1.9
1.6
Bernianamycin A
0.75
2.43
0.88
0.99
1.3
1.04
0.99
Althomycin
0.77
7.13
0.77
0.85
1.43
0.88
0.81
Thiocillin 1
0.99
11
7.5
1.43
1.34
2.34
2.12
G2
SKHEP-1
Conclusion and future aspects The current review emphasizes on new horizons of anticancer potential of thiazole based heterocyclic derivatives. Structural activity relationship studies and biological activity data of thiazoles establish them as possible multi-target enzyme inhibitors depicting their pharmacological potential through inhibition of some metabolic pathways. An increasing numbers of patents granted on thiazole-containing compounds and their exploration for possible clinical use in ongoing research and development reveal the potential of these derivatives in medicinal chemistry. Thus, it is clear from above that thiazole scaffold bearing compounds present plethora of applications in drug development for treatment against a variety of cancers. Despite remarkable advancements of thiazole-containing compounds, still some concerted research endeavors are requisite; •
Development of suitable synthesis protocols through application of green chemistry to provide a strong driving force for the future thiazole-containing compounds development.
89
•
The detailed elucidation of biological activity through investigation of mode of action especially on laboratory animals followed by clinical studies for the potent compounds.
•
A detailed study on pharmacodynamic and pharmacokinetic properties of listed potent compounds for anticancer activities.
•
Another attractive aspect is to work on identification and isolation of naturally occurring thiazole-containing compounds and antibiotics from plant and marine sources.
Since it is evident from this review that thiazole based compounds may be useful as inhibitors of multiple enzyme target inhibitors or some other metabolic pathways. Thorough investigation on adverse effects associated with thiazole-containing compounds can be a prospective area for scientific research. Development of superior analogs with better efficacy and pharmacokinetics and less side effects would be incredible contribution for the betterment of human beings. Conflict of interest Authors declare no conflict of interest. The authors alone are responsible for the content and writing of the paper. Acknowledgements Science and Engineering Research Board-Department of Science and Technology (SERBDST), Govt. of India is duly acknowledged for financial assistance under Fast Tract Scheme For Young Scientist (to Dr. Prabodh Chander Sharma) vide file No.: SB/FT/CS-134/2012 dated: July 15, 2014. Abbreviations: DNA
Deoxyribonucleic acid
LD50
cRNA
Complementary ribonucleic acid
NCI
lethal dose of a material that kill half of the sample population National Cancer Institute
IMP
Integral membrane protein
SAR
Structure activity relationship
B-RAF
Human gene that encodes a protein B-RAF
CNS
Central Nervous System
Bcr-Abl
Breakpoint cluster region proteinAbelson murine leukemia viral
TNF-α
Tumour Necrosis Factor receptor superfamily 90
oncogene EGFR
Epidermal growth factor receptor
µg/ml
Microgram per millilitre
TNBC
Triple-negative breast cancer
CA
Carbonic Anhydrase
MCF-7
Human breast cancer cell line
DPPH
HER-2
Human Epidermal Growth Factor Receptor 2
PI3K
2,2-Diphenyl-1picrylhydrazyl Phosphatidylinositol-4,5bisphosphate 3-kinase
MDAMB-468
A breast cancer cell line
P110α
IC50
Half maximal inhibitory concentration
RCC
EC50
Half maximal effective concentration
mTOR
CC50
50% cytotoxic concentration
VEGF
GI50
the concentration for 50% of maximal inhibition of cell proliferation
CAM
TGI50
concentration causing 0% growth inhibition
CDC
Complement Dependent Cytotoxicity
µg
Microgram
NF-ҡB
µM
Micromolar
Cdk
Protein complex (nuclear factor kappa-light-chainenhancer of activated B cells) Cyclin-dependent kinases
nM
Nanomolar
IR
Infrared
TGF-β
Transforming growth factor beta
NMR
Nuclear magnetic resonance
ALK
Anaplastic lymphoma kinase
IMP
integral membrane protein
Cys-751
Cysteine-751
IMPDH
Inosine 5'-monophosphate dehydrogenase
AIs
Aromatase inhibitors
NAD
Nicotinamide adenine dinucleotide
HAT
Histone acetylase
TAD
Topologically associating domains
HDAC
Histone deacetylase
Src-Abi
Oncogene; tyrosine kinase
SAHA
Suberoylanilide Hydroxamic Acid
CA-4
Combrestatin A-4
SMART
A new "smart" pill for advanced breast and bowel cancer
CA
Carbonic anhydrase
µmol/l
Micromole per liter
Kcal/mol Kilocalorie/mole
Phosphatidylinositol-4,5bisphosphate 3-kinase, catalytic subunit alpha Renal cell carcinoma Mechanistic target of rapamycin vascular endothelial growth factor Cell adhesion molecules
91
DMPM
Diffuse malignant peritoneal mesothelioma
∆Ψm
Mitochondrial membrane potential
References
[1]
B.G. Katzung, Basic & Clinical Pharmacology, 9th ed., Section VIII. Chemotherapeutic Drugs-Chapter 55. Published by Lange Medical Books, December 15th 2003, pp. 1276.
[2]
H.P. Rang, M.M Dale, J.M. Ritter, R.J. Flower, Rang and Dale’s Textbook of Pharmacology 6th ed., pp-718.
[3]
R. Majeed, A. Hamid, Y. Qurishi, A. K. Qazi, A. Hussain, M. Ahmed, R.A. Najar, J.A. Bhat, S.K. Singh, A.K. Saxena, Therapeutic targeting of cancer cell metabolism: role of metabolic enzymes, oncogenes and tumor suppressor genes, J. Cancer Sci. Ther. 4(9) (2012) 281-291.
[4]
L. Li, X. Zhou, W. Ching, P. Wang, Predicting enzyme targets for cancer drugs by profiling human metabolic reactions in NCI-60 cell lines, BMC Bioinformatics 11 (2010) 501.
[5]
R. Majeed, A. Hamid, Y. Qurishi, A.K. Qazi, A. Hussain, M. Ahmed, R.A. Najar, J.A. Bhat, S.K. Singh, A.K. Saxena, Therapeutic targeting of cancer cell metabolism: role of metabolic enzymes, oncogenes and tumor suppressor genes. J. Cancer Sci. Ther. 4(9) (2012) 281-291.
[6]
S. Kumar, M.K. Ahmad, M. Waseem, A.K. Pandey, Drug targets for cancer treatment: An overview, Med. Chem. 5(3) (2015) 115-123.
[7]
S.J. Conley, E. Gheordunescu, P. Kakarala, B. Newman, H. Korkaya, A.N. Heath, S.G. Clouthier, M.S. Wicha, Antiangiogenic agents increase breast cancer stem cells via the generation of tumour hypoxia, PNAS. 109(8) (2012) 2784-2789.
[8]
A.A.Vander Veldt, M. Lubberink, I. Bahce, M. Walraven, M.P. de Boer, H.N. Greuter, N.H. Hendrikse, J. Eriksson, A.D. Windhorst, P.E. Postmus, H.M. Verheul, E.H. Serne, A.A. Lammertsma, E.F. Smit, Rapid decrease in delivery of chemotherapy to tumours after anti-VEGF therapy: Implications for scheduling of anti-angiogenic drugs, Cancer Cell 21 (2012) 82-91.
[9]
H. Zahreddine, K.L. Borden, Mechanisms and insights into drug resistance in cancer, Front Pharmacol. 4 (2013) 1-8.
92
[10]
American
cancer
society.
Cancer
facts
and
figures
2018,
[https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and annual-cancer-facts-and-figures/2018/cancer-facts-and-figures-2018.pdf]
pp
1-76.
statistics/ (accessed
on
January 25, 2018). [11]
R. Scatena, P. Bottoni, A. Pontoglio, L. Mastrototaro, B. Giardina, Glycolytic enzyme inhibitors in cancer treatment, Expert Opin. Investig. Drugs 17(10) (2008) 1533-1545.
[12]
M.T. Chhabria, S. Patel, P. Modi, P.S. Brahmkshatriya, Thiazole: A review on chemistry, synthesis and therapeutic importance of its derivatives, Curr. Top. Med. Chem. 16(26) (2016) 2841-2862.
[13]
A.K. Jain, A. Vaidya, V. Ravichandran, S.K. Kashaw, R.K. Agrawal, Recent developments and biological activities of thiazolidinone derivatives: A review, Bioorg. Med. Chem. 20(11) (2012) 378-395.
[14]
M.V. Putz, C. Duda-Seiman, D. Duda-Seiman, A. Putz, I. Alexandrescu, M. Mernea, S. Avram, Chemical structure-biological activity models for pharmacophores’ 3Dinteractions, Int. J. Mol. Sci. 17 (2016) 1-23.
[15]
P.C. Sharma, K.K. Bansal, A. Deep, M. Pathak, Benzothiazole derivatives as potential anti-infective agents, Curr. Top. Med. Chem. 17(2) (2017) 208-237.
[16]
P.C. Sharma, A. Saini, K.K. Bansal, Synthesis of some thiazole clubbed heterocycles as possible antimicrobial and anthelmintic agents, Indian J. Heterocycl. Chem. 25(3-4) (2016) 303-310.
[17]
A. Ayati, S. Emami, A. Asadipour, A. Shafiee, A. Foroumadi, Recent applications of 1,3thiazole core structure in the identification of new lead compounds and drug discovery, Eur. J. Med. Chem. 97 (2015) 699-718.
[18]
P.C. Sharma, A. Jain, M. Shahar Yar, R. Pahwa, J. Singh, P. Chanalia, Novel fluoroquinolone
derivatives
bearing
N-thiomide
linkage
with
6-substituted-2-
aminobenzothiazoles: Synthesis and antibacterial evaluation, Arab. J. Chem. 10 (2017) S568-S575. [19]
B. Ghasemi, G. Sanjarani, Z. Sanjarani, H. Majidiani, Evaluation of anti-bacterial effects of some novel thiazole and imidazole derivatives against some pathogenic bacteria, Iran. J. Microbiol. 7(5) (2015) 281-286.
[20]
S. Khabnadideh, Z. Rezaei, K. Pakshir, K. Zomorodian, N. Ghafari, Synthesis and antifungal activity of benzimidazole, benzotriazole and aminothiazole derivatives, Res. Pharm. Sci. 7(2) (2012) 65-72.
93
[21]
J.M. Bueno, M. Carda, B. Crespo, A.C.Cunat, C. de Cozar, M.L.Leon, J.A. Marco, N. Roda, J.F. Sanz-Cervera, Design, synthesis and antimalarial evaluation of novel thiazole derivatives, Bioorg. Med. Chem. Lett. 26(16) (2016) 3938-3944.
[22]
A. Andreani, M. Granaiola, A. Leoni, A. Locatelli, R. Morigi, M. Rambaldi, Synthesis and antitubercular activity of imidazo[2,1-b]thiazoles, Eur. J. Med. Chem. 36(9) (2001) 743746.
[23]
K.W. Dawood, T.M. Eldebss, H.S. El-Zahabi, M.H. Yousef, Synthesis and antiviral activity of some new bis-1,3-thiazole derivatives, Eur. J. Med. Chem. 18(102) (2015) 266276.
[24]
R.N. Sharma, F.P. Xavier, K.K. Vasu, S.C. Chaturvedi, S.S. Pancholi, Synthesis of 4benzyl-1, 3-thiazole derivatives as potential anti-inflammatory agents: an analogue-based drug design approach, J. Enzyme Inhib. Med. Chem. 24(3) (2009) 890-897.
[25]
O. Bozdag-Dundar, M. Ceylan-Unlusoy, E.J. Verspohl, R. Ertan, Synthesis and antidiabetic activity of novel 2,4-thiazolidinedione derivatives containing a thiazole ring, ARZNEIMITTELFORSCH. 56(9) (2006) 621-625.
[26]
R.J. Weikert, S. Bingham Jr, M.A. Emanuel, E.B. Fraser-Smith, D.G. Loughhead, P.H. Nelson, A.L. Poulton, Synthesis and anthelmintic activity of 3'-benzoylurea derivatives of 6-phenyl-2,3,5,6-tetrahydroimidazo[2,1-b]thiazole, J. Med. Chem. 34(5) (1991) 16301633.
[27]
H. Ucar, K. Van derpoorten, S. Cacciaguerra, S. Spampinato, J.P. Stables, P. Depovere, M. Isa, B. Masereel, J. Delarge, J.H. Poupaert, Synthesis and anticonvulsant activity of 2(3H)-benzoxazolone and 2(3H)-benzothiazolone derivatives, J. Med. Chem. 41(7) (1998) 1138-1145.
[28]
B.Z. Kurt, I. Gazioglu, F. Sonmez, M. Kucukislamoglu, Synthesis, antioxidant and anticholinesterase activities of novel coumarylthiazole derivatives, Bioorg. Chem. 59 (2015) 80-90.
[29]
A. Lozynskyi, B. Zimenkovsky, R. Lesyk, Synthesis and anticancer activity of new thiopyrano [2, 3-d] thiazoles based on cinnamic acid amides, Sci. Pharm. 82(4) (2014) 723-733.
[30]
A.M. Omar, N.H. Eshba, Synthesis and biological evaluation of new 2,3-dihydrothiazole derivatives for antimicrobial, antihypertensive, and anticonvulsant activities, J. Pharm. Sci. 73(8) (1984) 1166-1168.
[31]
P. Franchetti,
L. Cappellacci, M. Grifantini, A. Barzi, G. Nocentini, H. Yang, A.
O'Connor, H.N. Jayaram, C. Carrell, B.M. Goldstein, Furanfurin and thiophenfurin: Two 94
novel tiazofurin analogues. Synthesis, structure, antitumour activity, and interactions with inosine monophosphate dehydrogenase, J. Med. Chem. 38(19) (1995) 3829-3837. [32]
X. Li, Y. He, C.H. Ruiz, M. Koenig, M.D. Cameron, Characterization of dasatinib and its structural analogs as CYP3A4 mechanism-based inactivators and the proposed bioactivation pathways, Drug Metab. Dispos. 37(6) (2009) 1242-1250.
[33]
S. Hu-Lieskovan, S. Mok, B. Homet Moreno, J. Tsoi, L. Robert, L. Goedert, E.M. Pinheiro, R.C. Koya, T.G. Graeber, B. Comin-Anduix, A. Ribas, Improved antitumour activity of immunotherapy with B-RAF and MEK inhibitors in B-RAF(V600E) melanoma, Sci. Transl. Med. 18,7(279) (2015) 279-41.
[34]
M.A. Rashid, K.R. Gustafson, J.H. Cardellina, M.R. Boyd, F. Patellamide, A new cytotoxic cyclic peptide from the colonial ascidian Lissoclinum patella, J. Nat. Products. 58(4) (1995) 594-597.
[35]
Y. Yao, S. Chen, X. Zhou, L. Xie, A. Chen, 5‑FU and ixabepilone modify the microRNA expression profiles in MDA‑MB‑453 triple‑negative breast cancer cells, Oncol. Lett. 7 (2014) 541-547.
[36]
K.H. Altmann, Epothilone B and its analogs - A new family of anticancer agents, Mini Rev. Med. Chem. 3(2) (2003) 149-158.
[37]
E. Ramadan, H.M. Hamid, S.A. Noureddin, K.O. Badahdah, Synthesis, characterization, and antitumor activity of some novel S-functionalized benzo[d]thiazole-2-thiol derivatives; regioselective coupling to the –SH group. J. Chem. Sci. 73(9) (2018) 647-654.
[38]
Y. Lu, C.M Li, Z. Wang, J. Chen, M.L. Mohler, W. Li, J.T. Dalton, D.D. Miller, Design, synthesis, and SAR studies of 4-substituted methoxylbenzoyl-aryl-thiazoles analogues as potent and orally bioavailable anticancer agents, J. Med. Chem. 54 (2011) 4678-4693.
[39]
R. Morigi, A. Locatelli, A. Leoni, M. Rambaldi, Recent patents on thiazole derivatives endowed with antitumour activity, Recent Pat. Anti-Cancer Drug Discov. 10 (2015) 280297.
[40]
H. He, X. Wang, L. Shi, W. Yin, Z. Yang, H. He, Y. Liang, Synthesis, antitumour activity and mechanism of action of novel 1,3-thiazole derivatives containing hydrazide-hydrazone and carboxamide moiety, Bioorg. Med. Chem. Lett. 26(14) (2016) 3263-3270.
[41]
Y. Lu, C. Li, Z. Wang, C.R. Ross, J. Chen, J. Dalton, W. Li, D.D. Miller, Discovery of 4substituted methoxybenzoyl-aryl-thiazole as novel anticancer agents: Synthesis, biological evaluation and structure-activity relationships, J. Med. Chem. 52(6) (2009) 1701-1711.
95
[42]
S.P. Shaik, V.L. Nayak, F. Sultana, A.V. Rao, A.B. Shaik, K.S. Babu, A. Kamal, Design and synthesis of imidazo[2,1-b]thiazole linked triazole conjugates: microtubuledestabilizing agents, Eur. J. Med. Chem. 126 (2017) 36-51.
[43]
T.I. Santana, M.O. Barbosa, P.A. Gomes, A.C. da Cruz, T.G. da Silva, A.C. Lima Leite. Synthesis, anticancer activity and mechanism of action of new thiazole derivatives, Eur. J. Med. Chem. 144 (2018) 874-886.
[44]
P. Lv, D. Li, Q. Li, X. Lu, Z. Xiao, H. Zhu. Synthesis, molecular docking and evaluation of thiazolyl-pyrazoline derivatives as EGFR TK inhibitors and potential anticancer agents, Bioorg. Med. Chem. Lett. 21 (2011) 5374-5377.
[45]
D. Secci, S. Carradori, B. Bizzarri, A. Bolasco, P. Ballario, Z. Patramani, P. Fragapane, S. Vernarecci, C. Canzonetta, P. Filetici, Synthesis of a novel series of thiazole-based histone acetyltransferase inhibitors, Bioorg. Med. Chem. 22(2014) 1680-1689.
[46]
S. Mirza, S.A. Naqvi, K.M. Khan, U. Salar, M.I. Choudhary, Facile synthesis of novel substituted aryl-thiazole (SAT) analogs via one pot multi-component reaction as potent cytotoxic agents against cancer cell lines, Bioorg. Chem. 70 (2017) 133-143.
[47]
M.A. Ewida, D.A. El Ella, D.S. Lasheen, H.A. Ewida, Y.I. El-Gazzar, H.I. El-Subbagh, Thiazolo[4,5-d]pyridazine analogues as a new class of dihydrofolate reductase (DHFR) inhibitors: Synthesis, biological evaluation and molecular modeling study, Bioorg. Chem. 74 (2017) 228-237.
[48]
V.K. Patel, A. Singh, D.K. Jain, A.K. Sharma, A.K. Gupta, P.C. Sharma, H. Rajak, Development of structure activity correlation model on 4-quinolones derivatives as tubulin polymerization inhibitors: rational to advance the understanding of structure activity profile, Drug Discov. Devel. 1(1) (2014) 1-16.
[49]
H. Rajak, A. Singh, K. Raghuwanshi, P.K. Dewangan, R. Veerasamy, P.C. Sharma, Dixit, P.A. Mishra, Structural insight into hydroxamic acid based histone deacetylase inhibitors for the presence of anticancer activity, Curr. Med. Chem. 21 (2014) 2642-2664.
[50]
D.K. Jain, A. Singh, V.K. Patel, P.C. Sharma, A.K. Gupta, A.K. Sharma, H. Rajak. Hydroxamic acid based histone deacetylase inhibitors: Present and future prospective as anticancer agent, Int. J. Pharm. Pharm. Sci. 6 (2014) 648-650.
[51]
P.C. Sharma, A. Sinhmar, A. Sharma, H. Rajak, D.P. Pathak, Medicinal Significance of Benzothiazole Scaffold: An Insight View, J. Enzyme Inhib. Med. Chem. 28(2) (2013) 240-266.
96
[52]
P.C. Sharma, M. Chaudhary, A. Sharma, A. Piplani, H. Rajak, O. Prakash, Insight View on Possible Role of Fluoroquinolones in Cancer Therapy, Curr. Top. Med. Chem. 13(16) (2013) 2076-2096.
[53]
H. Rajak, A. Singh, P.K. Dewangan, V. Patel, D.K. Jain, S.K. Tiwari, R. Veerasamy, P.C. Sharma, Peptide based macrocycles: Selective histone deacetylase inhibitors with antiproliferative activity, Curr. Med. Chem. 20 (2013) 1887-1903.
[54]
H. Rajak, P.K. Dewangan, V. Patel, D.K. Jain, A. Singh, R. Veerasamy, P.C. Sharma, A. Dixit. Design of combretastatin A4 analoges as tubulin target vascular disrupting agents with special emphasis on their Cis-restricted isomers, Curr. Pharm. Des. 19(10) (2013) 1923-1955.
[55]
H. Rajak, P. Kumar, P. Parmar, B.S. Thakur, R. Veerasamy, P.C. Sharma, A.K. Sharma, A.K. Gupta, J.S. Dangi, Appraisal of GABA and PABA as linker: Design and synthesis of novel benzamide based histone deacetylase inhibitors, Eur. J. Med. Chem. 53 (2012) 390397.
[56]
H. Rajak, A. Agarawal, P. Parmar, B.S. Thakur, R. Veerasamy, P.C. Sharma, M.D. Kharya, 2,5-Disubstituted-1,3,4-oxadiazoles / thiadiazole as surface recognition moiety: Design and synthesis of novel hydroxamic acid based histone deacetylase inhibitors, Bioorg. Med. Chem. Lett. 21 (2011) 5735-5738.
[57]
D. Griffith, P. Parker, C.J. Marmion, Enzyme inhibition as a key target for the development of novel metal-based anti-cancer therapeutics, Anticancer Agents Med. Chem. 10(5) (2010) 354-370.
[58]
S.K. Hanks, A.M. Quinn, T. Hunter, The protein kinase family: Conserved features and deduced phylogeny of the catalytic domains. Science 241(4861) (1988) 42-52.
[59]
M.K. Paul, A.K. Mukhopadhyay, Tyrosine kinase-role and significance in cancer, Int. J. Med. Sci. 1(2) (2004)101-115.
[60]
D.R. Robinson, Y.M. Wu, S.F. Lin, The protein tyrosine kinase family of the human genome, Oncogene 19(49) (2000) 5548-57.
[61]
E. Zwick, J. Bange, A. Ullrich, Receptor tyrosine kinase signalling as a target for cancer intervention strategies, Endocrine-related cancer 8(3) (2001) 161-73.
[62]
R.M. Strieter, Masters of angiogenesis, Nat. Med. 11 (2005) 925-7.
[63]
V.V. Padma, An overview of targeted cancer therapy, Biomedicine (Taipei) 5(4) (2015) 19. 97
[64]
R. Munagala, F. Aqil, R.C. Gupta, Promising molecular targeted therapies in breast cancer, Indian J. Pharmacol. 43(3) (2011) 236-45.
[65]
S.R. Hubbard, W.T. Miller, Receptor tyrosine kinases: mechanisms of activation and signalling, Curr. Opin. Cell Biol. 19(2) (2007) 117-123.
[66]
M.A. Lemmon, J. Schlessinger, Cell signaling by receptor tyrosine kinases, Cell 141(7) (2010) 1117-1134.
[67]
P. Seshacharyulu, M.P. Ponnusamy, D. Haridas, M. Jain, A.K. Ganti, S.K. Batra, Targeting the EGFR signaling pathway in cancer therapy, Expert Opin. Ther. Tar. 16(1) (2012) 15-31.
[68]
J. Carlsson, H. Nordgren, J. Sjostrom, K. Wester, K. Villman, N.O. Bengtsson, B. Ostenstad, H. Lundqvist, C. Blomqvist, HER2 expression in breast cancer primary tumours and corresponding metastases, Original data and literature review, British J. Cancer 90(12) (2004) 2344-8.
[69]
A. Sebastian, V. Pandey, C.D. Mohan, Y.T. Chia, S. Rangappa, J. Mathai, C.P. Baburajeev, S. Paricharak, L.H. Mervin, K.C. Bulusu, J.E. Fuchs, A. Bender, S. Yamada, Basappa, P.E. Lobie, K.S. Rangappa, Novel adamantanyl-based thiadiazolyl pyrazoles targeting EGFR in triple-negative breast cancer, ACS Omega 1 (2016) 1412-1424.
[70]
H. Wang, K. Qiu, H. Cui, Y. Yang, Yin-Luo, M. Xing, X. Qiu, L. Bai, H. Zhu, Synthesis, molecular docking and evaluation of thiazolyl-pyrazoline derivatives containing benzodioxole as potential anticancer agents, Bioorg. Med. Chem. 21 (2013) 448-455.
[71]
H. Ding, Z. Chen, C. Zhang, T. Xin, Y. Wang, H. Song, Y. Jiang, Y. Chen, Y. Xu, C. Tan, Synthesis and cytotoxic activity of some novel N-pyridinyl-2-(6-phenylimidazo[2,1b]thiazol-3-yl)acetamide derivatives, Molecules 17 (2012) 4703-4716.
[72]
P.C. Lv, C.F. Zhou, J. Chen, P.G. Liu, K.R. Wang, W.J. Mao, H.O. Li, Y. Yang, J. Xiong, H.L Zhu, Design, synthesis and biological evaluation of thiazolidinone derivatives as potential EGFR and HER-2 kinase inhibitors, Bioorg. Med. Chem. 18 (2010) 314-319.
[73]
U. Bhanushali, S. Rajendran, K. Sarma, P. Kulkarni, K. Chatti, S. Chatterjee, C.S. Ramaa, 5-Benzylidene-2,4-thiazolidenedione derivatives: Design, synthesis and evaluation as inhibitors of angiogenesis targeting VEGR-2, Bioorg. Chem. 67 (2016) 139-147.
[74]
E. Gonzalez, T.E. McGraw, The Akt kinases: isoform specificity in metabolism and cancer, Cell Cycle 8(16) (2009) 2502-2508.
98
[75]
A. Bellacosa, C.C. Kumar, A. Di Cristofano, J.R. Testa, Activation of AKT kinases in cancer: implications for therapeutic targeting, Adv. Cancer Res. 94 (2005) 29-86.
[76]
S. Chang, Z. Zhang, X. Zhuang , J. Luo, X. Cao, H. Li, Z. Tu, X. Lu, X. Ren, K. Ding, New thiazole carboxamides as potent inhibitors of Akt kinases, Bioorg. Med. Chem. Lett. 22 (2012) 1208-1212.
[77]
M.D. Altıntop, B. Sever, C. G. Akalın, A. Ozdemir, Design, synthesis, and evaluation of a new series of thiazole-based anticancer agents as potent Akt Inhibitors, Molecules 23 (2018) 1318.
[78]
L.E. Ling, W.C. Lee. Tgf-beta type I receptor (Alk5) kinase inhibitors in oncology, Curr. Pharm. Biotechnol. 12(12) (2011) 2190-202.
[79]
D. Kim, J.H. Choi, Y.J. Ana, H.S. Lee, Synthesis and biological evaluation of 5-(pyridin2-yl) thiazoles as transforming growth factor-b type1 receptor kinase inhibitors, Bioorg. Med. Chem. Lett. 18 (2008) 2122-2127.
[80]
H. Amada, Y. Sekiguchi, N. Ono, T. Koami, T. Takayama, T. Yabuuchi, H. Katakai, A. Ikeda, M. Aoki, T. Naruse, R. Wada, A. Nozoe, M. Sato, 5-(1,3-Benzothiazol-6-yl)-4-(4methyl-1,3-thiazol-2-yl)-1H-imidazole derivatives as potent and selective transforming growth factor-β type I receptor inhibitors, Bioorg. Med. Chem. 20(24) (2012) 7128-38.
[81]
H. Amada, Y. Sekiguchi, N. Ono, Y. Matsunaga, T. Koami, H. Asanuma, F. Shiozawa, M. Endo, A. Ikeda, M. Aoki, N. Fujimoto, R. Wada, M. Sato, Design, synthesis, and evaluation of novel 4-thiazolylimidazoles as inhibitors of transforming growth factor-β type I receptor kinase. Bioorg. Med. Chem. Lett. 22(5) (2012) 2024-2029.
[82]
S. Gaillard, V. Stearns, Aromatase inhibitor-associated bone and musculoskeletal effects: new evidence defining etiology and strategies for management, Breast Cancer Res. 13(2) (2011) 1-11.
[83]
M.J. Balunas, B. Su, R.W. Brueggemeier, A.D. Kinghornb, Natural products as aromatase inhibitors, Anticancer Agents Med. Chem. 8(6) (2008) 646-682.
[84]
S. Abdelrahman, A.S. Mayhoub, L. Marler, P. Tamara, T.P. Kondratyuk, Park Eun-Jung, M. John, J.M. Pezzuto, M. Cushman,Optimization of the aromatase inhibitory activities of pyridylthiazole analogues of resveratrol, Bioorg. Med. Chem. 20 (2012) 2427-2434.
[85]
T.T. Tunga, D.T. Oanha, P.T. Dunga, V.T. Huea, H.H. Parkb, B.W. Hanb, Y. Kimc, J.T. Hongc, S.B. Han, N.H. Nam, New Benzothiazole/thiazole-containing hydroxamic acids as potent histone deacetylase inhibitors and antitumour agents, Med. Chem. 9 (2013) 10511057.
99
[86]
S. Anandan, J.S. Ward, R.D. Brokx, T. Denny, M.R. Bray, D.V. Patel, X. Xiao, Design and synthesis of thiazole-5-hydroxamic acids as novel histone deacetylase inhibitors, Bioorg. Med. Chem. Lett. 17 (2007) 5995-5999.
[87]
S. Carradori, D. Rotili, C. De Monte, A. Lenoci, M. D’Ascenzio, V. Rodriguez, P. Filetici, M. Miceli, A. Nebbioso, L. Altucci, D. Secci, A. Mai, Evaluation of a large library of (thiazol-2-yl) hydrazones and analogues as histone acetyltransferase inhibitors: Enzyme and cellular studies, Eur. J. Med. Chem. 80 (2014) 569-578.
[88]
D.T.K. Oanh, H.V. Hai, S.H. Park, H. Kim, B. Han, H. Kim, J. Hong, S. Han,V.T.M. Hue, N. Nam, Benzothiazole-containing hydroxamic acids as histone deacetylase inhibitors and antitumour agents, Bioorg. Med. Chem. Lett. 21 (2011) 7509-7512.
[89]
M.Y. Zhao, Y. Yin, X. Yu, C.B. Sangani, S. Wanga, A. Lu, L. Yang, P. Lv, M. Jiang, H. Zhu, Synthesis, biological evaluation and 3D-QSAR study of novel 4,5-dihydro-1Hpyrazole thiazole derivatives as B-RAF(V600E) inhibitors, Bioorg. Med. Chem. 23 (2015) 46-54.
[90]
M.S. Abdel-Maksoud, M.R. Kim, M.I. El-Gamal, M.M. Gamal El-Din, J. Tae, H.S. Choi, K. Lee, K.H. Yoo, C. Oh, Design, synthesis, in vitro antiproliferative evaluation, and kinase inhibitory effects of a new series of imidazo[2,1-b]thiazole derivatives, Eur. J. Med. Chem. 95 (2015) 453-463.
[91]
F. Musumeci, S. Schenone, C. Brullo, M. Botta, An update on dual Src/Abl inhibitors, Future Med. Chem. 4(6) (2012) 799-822.
[92]
J. Cai, M. Sun, X. Wu, J. Chen, P. Wang, X. Zong, M. Ji, Design and synthesis of novel 4benzothiazole amino quinazolines dasatinib derivatives as potential anti-tumour agents, Eur. J. Med. Chem. 63 (2013) 702-712.
[93]
L.J. Lombardo, F.Y. Lee, P. Chen, D. Norris, J.C. Barrish, K. Behnia, S. Castaneda, L.A.M. Cornelius, J. Das, A.M. Doweyko, C. Fairchild, J.T. Hunt, I. Inigo, K. Johnston, A. Kamath, D. Kan, H. Klei, P. Marathe, S. Pang, R. Peterson, S. Pitt, G.L. Schieven, R.J. Schmidt, J. Tokarski, M. Wen, J. Wityak, R.M. Borzilleri, Discovery of N-(2-Chloro-6methyl-phenyl)-2-(6-(4-(2-hydroxyethyl)-piperazin-1-yl)-2-methylpyrimidin-4- ylamino) thiazole-5-carboxamide (BMS-354825), A dual Src/Abl kinase inhibitor with potent antitumour activity in preclinical assays, J. Med. Chem. 47 (2004) 6658-6661.
[94]
E. Mukhtar, V.M. Adhami, H. Mukhtar, Targeting microtubules by natural agents for cancer therapy, Mol. Cancer Ther. 13(2) (2014) 275-284.
[95]
C. Dumontet, M.A. Jordan, Microtubule-binding agents: a dynamic field of cancer therapeutics, Nat. Rev. Drug Discov. 9(10) (2010) 790-803. 100
[96]
A.L. Parker, M. Kavallaris, J.A. McCarroll, Microtubules and their role in cellular stress in cancer, Front Oncol. 4 (2014) 153.
[97]
A. Kryshchyshyn, D. Atamanyuk, R. Lesyk, Fused thiopyrano [2, 3-d] thiazole derivatives as potential anticancer agents, Sci. Pharm. 80 (2012) 509-529.
[98]
K. Ohsumi, T. Hatanaka, K. Fujita, R. Nakagawa, Y. Fukuda, Y. Nihei, Y. Suga, Y. Morinaga, Y. Akiyama, T. Tsuji, Syntheses and antitumour activity of cis-restricted combretastatins: 5-Membered heterocyclic analogues, Bioorg. Med. Chem. Lett. 8 (1998) 3153-3158.
[99]
R. Romagnoli, P.G. Baraldi, M.K. Salvador, M.E. Camacho, D. Preti, M.A. Tabrizi, M. Bassetto, A. Brancale, E. Hamel, R. Bortolozzi, G. Basso, G. Viola, Synthesis and biological evaluation of 2-substituted-4-(3’,4’,5’-trimethoxy phenyl)-5-aryl thiazoles as anticancer agents, Bioorg. Med. Chem. 20 (2012) 7083-7094.
[100] Z. Liu, Y. Wang, Z. Li, J. Jiang, D. Boykin, Synthesis and anticancer activity of novel 3, 4-diarylthiazol-2(3H)-ones (imines), Bioorg. Med. Chem. Lett. 19 (2009) 5661-5664. [101] A.V. Rao, K. Swapna, S.P. Shaik, V.L. Nayak, T.S. Reddy, S. Sunkari, T.B. Shaik, C. Bagul, A. Kamal, Synthesis and biological evaluation of cis-restricted triazole/tetrazole mimics of combretastatin-benzothiazole hybrids as tubulin polymerization inhibitors and apoptosis inducers, Bioorg. Med. Chem. 25 (2017) 977-999. [102] M. Sun, Q. Xu, J. Xu, Y. Wu, Y. Wang, D. Zuo, Q. Guan, K. Bao, J. Wang, Y. Wu, W. Zhang, Synthesis and bio-evaluation of N,4-diaryl-1,3-thiazole-2-amines as tubulin inhibitors with potent antiproliferative activity, Plos One 12(3) (2017) 1-15. [103] T.B. Shaik, S.M.A Hussaini, V.L. Nayak, M.L. Sucharitha, M.S. Malik, A. Kamal. Rational design and synthesis of 2-anilinopyridinyl-benzothiazole schiff bases as antimitotic agents, Bioorg. Med. Chem. Lett. 27 (2017) 2549-2558. [104] M. Banimustafa, A. Kheirollahi, M. Safavi, S.K. Ardestani, H. Aryapour, A. Foroumadi, S. Emami, Synthesis and biological evaluation of 3-(trimethoxyphenyl)-2(3H)-thiazole thiones as combretastatin analogs, Eur. J. Med. Chem. 70 (2013) 692-702. [105] S.P. Shaik, M. Vishnuvardhan, F. Sultana, A.V.S. Rao, C. Bagul, D. Bhattacharjee, J.S. Kapure, N. Jain, A. Kamal, Design and synthesis of 1,2,3-triazolo linked benzo[d]imidazo[2,1-b]thiazole conjugates as tubulin polymerization inhibitors, Bioorg. Med. Chem. 2017. [Article in Press]. [106] M. Salehi, M. Amini, S.N. Ostad , G.H. Riazi, A. Assadieskandar, B. Shafiei, A. Shafiee, Synthesis, cytotoxic evaluation and molecular docking study of 2-alkylthio-4-(2,3,4-
101
trimethoxyphenyl)-5-aryl-thiazoles as tubulin polymerization inhibitors, Bioorg. Med. Chem. 21 (2013) 7648-7654. [107] S.D. Guggilapu, L. Guntuku, T.S. Reddy, A. Nagarsenkar, D.K. Sigalapalli, V.G.M. Naidu, S.K. Bhargava, N.B. Bathini, Synthesis of thiazole linked indolyl-3-glyoxylamide derivatives as tubulin polymerization inhibitors, Eur. J. Med. Chem. 138 (2017) 83-95. [108] M.F. Baig, V.L. Nayak, P. Budaganaboyina, K. Mullagiri, S. Sunkari, J. Gour, A. Kamal. Synthesis and biological evaluation of imidazo [2, 1-b] thiazole benzimidazole conjugates as microtubule-targeting agents, Bioorg. Chem. 77 (2018) 515-526. [109] F. Wang, Z. Yang, Y. Liu, L. Ma, Y. Wu, L. He, M. Shao, K. Yu, W. Wu, Y. Pu, C. Nie, L. Chen, Synthesis and biological evaluation of diarylthiazole derivatives as antimitotic and antivascular agents with potent antitumour activity, Bioorg. Med. Chem. 23 (2015) 3337-3350. [110] J.C. Wang, Cellular roles of DNA topoisomerases: a molecular perspective, Nat. Rev. Mol. Cell Biol. 3 (2002) 430-440. [111] J.L. Nitiss, DNA topoisomerase II and its growing repertoire of biological functions. Nat. Rev. Cancer 9(5) (2009) 327–337. [112] S. Choi, H.J. Park, S.K. Lee, S.W. Kim, G. Han, H.P. Choo, Solid phase combinatorial synthesis of benzothiazoles and evaluation of topoisomerase II inhibitory activity, Bioorg. Med. Chem. 14 (2016) 1229-1235. [113] Y. Cheng, S.R. Avula, W. Gao, D. Addla, V.K.R. Tangadanchu, L. Zhang, J. Lin, C. Zhou,
Multi-targeting exploration of new 2-aminothiazolyl quinolones: Synthesis,
antimicrobial evaluation, interaction with DNA, combination with topoisomerase IV and penetrability into cells, Eur. J. Med. Chem. 124 (2016) 935-945. [114] A. Beauchard, A. Jaunet, L. Murillo, B. Baldeyrou, A. Lansiaux, J. Cherouvrier, L. Domon, L. Picot, C. Bailly, T. Besson, V. Thiery, Synthesis and antitumoural activity of novel
thiazolobenzotriazole,
thiazoloindolo[3,2-c]quinoline
and
quinolinoquinoline
derivatives, Eur. J. Med. Chem. 44 (2009) 3858-3865. [115] A. Reichelt , J.M. Bailis, M.D. Bartberger, G. Yao, H. Shu, M.R. Kaller, J.G. Allen, M.F. Weidner, K.S. Keegan, J.H. Dao, Synthesis and structure activity relationship of trisubstituted thiazoles as Cdc7 kinase inhibitors, Eur. J. Med. Chem. 80 (2014) 364-382. [116] O. Afzal, M.S. Akhtar, S. Kumar, M.R. Ali, M. Jaggi, S. Bawa, Hit to lead optimization of a series of N-[4-(1,3-benzothiazol-2-yl)phenyl]acetamides as monoacylglycerol lipase inhibitors with potential anticancer activity, Eur. J. Med. Chem. 121 (2016) 318-330.
102
[117] F. Lefranc, Z. Xu, P. Burth, V. Mathieu, G. Revelant, M.V. de Castro Faria, C. Noyon, D.G. Garcia, D. Dufour, C. Bruyere, C.F. Gonçalves-de-Albuquerque, P.V. Antwerpen, B. Rogister, S. Hesse, G. Kirsch, R. Kiss, 4-Bromo-2-(piperidin-1-yl)thiazol-5-yl-phenyl methanone (12b) inhibits Na+/K+-ATPase and Ras oncogene activity in cancer cells, Eur. J. Med. Chem. 63 (2013) 213-223. [118] D.A. Ibrahim, D.S. Lasheen, M.Y. Zaky, A.W. Ibrahim, D. Vullo, M. Ceruso, C.T. Supuran, D.A. El Ella, Design and synthesis of benzothiazole-6-sulfonamides acting as highly potent inhibitors of carbonic anhydrase isoforms I, II, IX and XII, Bioorg. Med. Chem. 23 (2015) 4989-4999. [119] S.K. Suthar, S. Bansal, S. Lohan, V. Modak, A. Chaudhary, A. Tiwari, Design and synthesis of novel 4-(4-oxo-2-arylthiazolidin-3-yl) benzenesulfonamides as selective inhibitors of carbonic anhydrase IX over I and II with potential anticancer activity, Eur. J. Med. Chem. 66 (2013) 372-379. [120] D. Vogt, J. Weber, K. Ihlefeld, A. Bruggerhoff, E. Proschak, H. Stark, Design, synthesis and evaluation of 2-aminothiazole derivatives as sphingosine kinase inhibitors, Bioorg. Med. Chem. 22 (2014) 5354-5367. [121] P. Franchetti, L. Cappellacci, M. Pasqualini, R. Petrelli, V. Jayaprakasan, H.N. Jayaram, D.B. Boyd, M.D. Jaind, M. Grifantinia. Synthesis, conformational analysis, and biological activity of new analogues of thiazole-4-carboxamide adenine dinucleotide (TAD) as IMP dehydrogenase inhibitors, Bioorg. Med. Chem. 13 (2005) 2045-2053. [122] H. Zhao, G. Cui, J. Jin, X. Chen, B. Xu, Synthesis and Pin1 inhibitory activity of thiazole derivatives, Bioorg. Med. Chem. 24 (2016) 5911-5920. [123] C. Chen, J. Song, J. Wanga, C. Xu, C. Chen, W. Gu, H. Sun, X. Wena, Synthesis and biological evaluation of thiazole derivatives as novel USP7 Inhibitors, Bioorg. Med. Chem. Lett. 27 (2017) 845-849. [124] L. Yan, N. Rosen, C. Arteaga, Targeted therapies: A new generation of cancer treatments, Chin. J. Cancer 30(1) (2011) 1-4. [125] D. Kaminskyy, G.J.M. den Hartog, M. Wojtyra, M. Lelyukh, A. Gzella, A. Bast, R. Lesyk, Antifibrotic and anticancer action of 5-ene amino/Iminothiazolidinones, Eur. J. Med. Chem. 112 (2016) 180-195. [126] R.S. Giri, H.M. Thaker, T. Giordano, B. Chen, S. Nuthalapaty, K.K. Vasu, V. Sudarsanam, Synthesis and evaluation of quinazolinone derivatives as inhibitors of NFkB, AP-1 mediated transcription and eIF-4E mediated translational activation: Inhibitors of multi-pathways involve in cancer, Eur. J. Med. Chem. 45 (2010) 3558-3563. 103
[127] L. Xie, J. Huanga, X. Chena, H. Yu, K. Lia, D. Yang, X. Chen, J. Ying, F. Pan, Y. Lv, Y. Cheng, Design, synthesis and biological evaluation of novel rapamycin benzothiazole hybrids as mTOR targeted anti-cancer agents, Chem. Pharm. Bull. 64(4) (2016) 346-55. [128] A.R. Ali, E.R. El-Bendary, M.A. Ghaly, I.A. Shehata, Synthesis, in vitro anticancer evaluation and in silico studies of novel imidazo[2,1-b]thiazole derivatives bearing pyrazole moieties, Eur. J. Med. Chem. 75 (2014) 492-500. [129] X. Xie, H. Li, J. Wang, S. Mao, M. Xin, S. Lu, Q. Mei, S. Zhang, Synthesis and anticancer effects
evaluation
of
1-alkyl-3-(6-(2-methoxy-3-sulfonylaminopyridin-5-
yl)benzo[d]thiazol-2-yl)urea as anticancer agents with low toxicity, Bioorg. Med. Chem. 23 (2015) 6477-6485. [130] H. Li, X. Wang, J. Wang, T. Shao, Y. Li, Q. Mei, S. Lu, S. Zhang, Combination of 2methoxy-3-phenylsulfonylaminobenzamide and 2-aminobenzothiazole to discover novel anticancer agents, Bioorg. Med. Chem. 22 (2014) 3739-3748. [131] M. Hayakawa, H. Kaizawa, K. Kawaguchi, N. Ishikawa, T. Koizumi, T. Ohishi, M. Yamano, M. Okada, M. Ohta, S. Tsukamoto, F. Raynaud, M.D. Waterfield, P. Parkerd, P. Workman, Synthesis and biological evaluation of imidazo[1,2-a]pyridine derivatives as novel PI3 kinase p110a inhibitors, Bioorg. Med. Chem. 15 (2007) 403-412. [132] R.A. Fairhurst, M. Gerspacher, P. Imbach-Weese, R. Mah, G. Caravatti, P. Furet, C. Fritsch, C. Schnell, J. Blanz, F. Blasco, S. Desrayaud, D.A. Guthy, M. Knapp, D. Arz, J. Wirth, E. Roehn-Carnemolla, V.H Luu, Identification and optimisation of 4,5dihydrobenzo [1,2-d:3,4-d]bisthiazole and 4,5-dihydrothiazolo[4,5-h]quinazoline series of selective phosphatidylinositol-3 kinase alpha inhibitors, Bioorg. Med. Chem. Lett. 25 (2015) 3575-3581. [133] S. Xuejiao, X. Yong, W. Ningyu, Z. Lidan, S. Xuanhong, X. Youzhi, Y. Tinghong, S. Yaojie, Z. Yongxia, Y. Luoting, A novel benzothiazole derivative YLT322 induces apoptosis via the mitochondrial apoptosis pathway in vitro with anti-tumour activity in solid malignancies, Plus One 8(5) (2013) 1-10. [134] M. Choi, K.H. Jung, D. Kim, H. Lee, H. Zheng, B.H. Park, S. Hong, M. Kim, S. Hong, S. Hong, Anticancer effects of a novel compound HS-113 on cell growth, apoptosis, and angiogenesis in human hepatocellular carcinoma cells, Cancer Lett. 306 (2011) 190-196. [135] M.P. Tantaka, D.D. Mukherjee, A. Kumar, G. Chakrabarti, D. Kumar, A facile and microwave-assisted rapid synthesis of 2-arylamino-4-(3′-indolyl)-thiazoles as apoptosis inducing cytotoxic agents, Anti-Cancer Agents Med. Chem. 17 (2017) 442-455.
104
[136] G. Lotfy, M.M. Said, E.S. Ashry, E.S. El Tamany, A. Al-Dhfyan, Y.M. Abdel Aziz, A. Barakat, Synthesis of new spirooxindole-pyrrolothiazole derivatives: Anti-cancer activity and molecular docking, Bioorg. Med. Chem. 25 (2017) 1514-1523. [137] P. Kumar, M. Duhan, K. Kadyan, J.K. Bhardwaj, P. Saraf, M. Mittal, Multicomponent synthesis of some molecular hybrid containing thiazole pyrazole as apoptosis inducer, Drug Res. (Stuttg) 68(2) (2018) 72-79. [138] S.M.M. Yahya, A.O. Abdelhamid, M.M. Abd-Elhalima, G.H. Elsayeda, E.F. Eskandera, The effect of newly synthesized progesterone derivatives on apoptotic and angiogenic pathway in MCF-7 breast cancer cells. Steroids 126 (2017) 15-23. [139] W. Zhou, W. Tang, Z. Sun, Y. Li, Y. Dong, H. Pei, Y. Peng, J. Wang, T. Shao, Z. Jiang, Z. Zhen Yi, Y. Chen, Discovery and optimization of N-substituted 2-(4-pyridinyl) thiazole carboxamides against tumour growth through regulating angiogenesis signaling pathways, Sci. Rep. 6 (2016) 33-34. [140] A. Andreani, M. Granaiola, A. Leoni, A. Locatelli, R. Morigi, M. Rambaldi, L. Varoli, D. Lannigan, J. Smith, D. Scudiero, S. Kondapaka, R.H. Shoemaker, Imidazo[2,1-b]thiazole guanylhydrazones as RSK2 inhibitors, Eur. J. Med. Chem. 46 (2011) 4311-4323. [141] N.J. Wheate, C.R. Brodie, J.G. Collins, S. Kemp, J.R. Aldrich-Wright, DNA intercalators in cancer therapy: organic and inorganic drugs and their spectroscopic tools of analysis, Mini Rev. Med. Chem. 7(6) (2007) 627-48. [142] A. Grozav, L.I. Gaina, V. Pileczki, O. Crisan, L. Silaghi-Dumitrescu, B. Therrien, V. Zaharia, I. Berindan-Neagoe, The synthesis and antiproliferative activities of new arylidene-hydrazinyl-thiazole derivatives, Int. J. Mol. Sci. 15 (2014) 22059-22072. [143] F.J. Reyes-Rangel , A.K. Lopez-Rodriguez, L.V. Pastrana-Cancino, M.A. Loza-Mejia, J.D. Solano, R. Rodriguez-Sotres, A. Lira-Rocha, Synthesis, cytotoxic activity, DNA binding and molecular docking studies of novel 9-anilinothiazolo[5,4-b]quinoline derivatives, Med. Chem. Res. 25 (2016) 2976-2988. [144] V.M. Manikandamathavan, M. Thangaraj, T. Weyhermuller, R.P. Parameswari, V. Punitha, N.N. Murthy, B.U. Nair, Novel mononuclear Cu (II) terpyridine complexes, Impact of fused ring thiophene and thiazole head groups towards DNA/BSA interaction, cleavage and antiproliferative activity on HEPG2 and triple negative CAL-51 cell line, Eur. J. Med. Chem. 135 (2017) 434-446. [145] N. Fan, Q. He, M. Duan, Y. Bai, J. Tang, Synthesis and antiproliferative activity of D-ring substituted steroidal benzamidothiazoles, Steroids 112 (2016) 103-108.
105
[146] K. Kotthireddy, S. Devulapally, A. Pasula, An efficient one-pot three-component synthesis of 2-(4-(2-oxo-2H-chromen-3-yl)thiazol-2-yl)-3-arylacrylonitriles and their cytotoxic activity evaluation with molecular docking, J. Saudi Chem. Soc. 23 (2019) 325-337. [147] A. Mohammadi-Farani, A. Foroumadi, M.R. Kashani, A. Aliabadi, N-Phenyl-2-ptolylthiazole-4-carboxamide derivatives: Synthesis and cytotoxicity evaluation as anticancer agents, Iran. J. Basic Med. Sci. 17 (2014) 502-508. [148] A. Zablotskaya, I. Segal, A. Geronikaki, T. Eremkina, S. Belyakov, M. Petrova, I. Shestakova, L. Zvejniece, V. Nikolajeva, Synthesis, physicochemical characterization, cytotoxicity, antimicrobial, anti-inflammatory and psychotropic activity of new N-[1,3(benzo)thiazol-2-yl]-ω-[3,4-dihydroisoquinolin-2(1H)-yl] alkanamides, Eur. J. Med. Chem. 70 (2013) 846-856. [149] A. Cohen, M.D. Crozet, P. Rathelot, N. Azas, P. Vanelle, Synthesis and promising in vitro antiproliferative activity of sulfones of a 5-nitrothiazole series, Molecules 18 (2013) 97113. [150] A. Carbone, B. Parrino, G. Di Vita, A. Attanzio, V. Spano, A. Montalbano, P. Barraja, L. Tesorierev, P. Livrea MA Diana, G. Cirrincione, Synthesis and antiproliferative activity of thiazolyl-bis-pyrrolo[2,3-b]pyridines
and
indolyl-thiazolyl-pyrrolo[2,3-c]pyridines,
Nortopsentin analogues, Mar. Drugs 13 (2015) 460-492. [151] W. Cai, A. Liu, Z. Li, W. Dong, X. Liu, N. Sun, Synthesis and anticancer activity of novel thiazole-5-carboxamide derivatives, Appl. Sci. 6(8) (2016) 1-10. [152] A. Fallah-Tafti, A. Foroumadi, R. Tiwari, A.N. Shirazi, D. Hangauer, Y. Bu, T. Akbarzadeh, K. Parang, A. Shafiee, Thiazolyl N-benzyl-substituted acetamide derivatives: Synthesis, Src kinase inhibitory and anticancer activities, Eur. J. Med. Chem. 46 (2011) 4853-4858. [153] A.T. Taher,
H.H. Georgey, H.I. El-Subbagh, Novel 1,3,4-heterodiazole analogues:
Synthesis and in-vitro antitumour activity, Eur. J. Med. Chem. 47 (2012) 445-451. [154] C. Yeh, C. Su, J. Hwang, M. Chou, Therapeutic effects of cantharidin analogues without bridging ether oxygen on human hepatocellular carcinoma cells, Eur. J. Med. Chem. 45 (2010) 3981-3985. [155] E. Gursoy, N.U. Guzeldemirci, Synthesis and primary cytotoxicity evaluation of new imidazo [2, 1-b] thiazole derivatives, Eur. J. Med. Chem. 42 (2007) 320-326. [156] D.S. Prasanna, C.V. Kavitha, K. Vinaya, S.R. Ranganatha, S. Raghavan, K.S. Rangappa, Synthesis and Identification of a new class of antileukemic agents containing 2-
106
(arylcarboxamide)-(S)-6-amino-4,5,6,7-tetrahydrobenzo[d]thiazole, Eur. J. Med. Chem. 45 (2010) 5331-5336. [157] D. Havrylyuk, B. Zimenkovsky, O. Vasylenko, L. Zaprutko, A. Gzella, R. Lesyk, Synthesis of novel thiazolone-based compounds containing pyrazoline moiety and evaluation of their anticancer activity, Eur. J. Med. Chem. 44 (2009) 1396-1404. [158] E.L. Luzina, A.V. Popov, Synthesis and anticancer activity of N-bis (trifluoromethyl) alkyl-N’-thiazolyl and N-bis (trifluoromethyl) alkyl-N’-benzothiazolyl ureas, Eur. J. Med. Chem. 44 (2009) 4944-4953. [159] F.A. Al-Omary, G.S. Hassan, S.M. El-Messery, H.I. El-Subbagh, Substituted thiazoles V. Synthesis and antitumour activity of novel thiazolo[2,3-b]quinazoline and pyrido[4,3d]thiazolo[3,2-a]pyrimidine analogues, Eur. J. Med. Chem. 47 (2012) 65-72. [160] B. Chen, R. Zhao, B. Wang, R. Droghini, J. Lajeunesse, P. Sirard, M. Endo, B. Balasubramanian, J.C. Barrisha, A new and efficient preparation of 2-aminothiazole-5carbamides, Applications to the synthesis of the anti-cancer drug dasatinib. ARKIVOC. (vi) (2010) 32-38. [161] F.L. Gouveia, R.M.B. De Oliveira, T.B. De Oliveira, I.M. Da Silva, S.C. Do Nascimento, K.X.F.R. De Sena, J.F.C. De Albuquerque, Synthesis, antimicrobial and cytotoxic activities of some 5-arylidene-4-thioxo-thiazolidine-2-ones, Eur. J. Med. Chem. 44 (2009) 2038-2043. [162] G.A. Elmegeed, W.K.B. Khalil, R.M. Mohareb, H.H. Ahmed, M.M. Abd-Elhalim, G.H. Elsayed, Cytotoxicity and gene expression profiles of novel synthesized steroid derivatives as chemotherapeutic anti-breast cancer agents, Bioorg. Med. Chem. 19 (2011) 6860-6872. [163] G.S. Hassan, S.M. El-Messery, F.A. Al-Omary, S.T. Al-Rashood, M.I. Shabayek, Y.S. Abulfadl, E.E. Habib, S.M. El-Hallouty, W. Fayad, K.M. Mohamed, B.S. El-Menshawi, H.I. El-Subbagh, Nonclassical antifolates, part 4. 5-(2-Aminothiazol-4-yl)-4-phenyl-4H1,2,4-triazole-3-thiols as a new class of DHFR inhibitors, Synthesis, biological evaluation and molecular modelling study, Eur. J. Med. Chem. 66 (2013) 135-145. [164] G.S. Hassan, S.M. El-Messery, F.A. Al-Omary, H.I. El-Subbagh, Substituted thiazoles VII. Synthesis and antitumour activity of certain 2-(substituted amino)-4-phenyl-1,3thiazole analogs, Bioorg. Med. Chem. Lett. 22 (2012) 6318-6323. [165] H.M. Refaat, Synthesis and anticancer activity of some novel 2-substituted benzimidazole derivatives, Eur. J. Med. Chem. 45 (2010) 2949-2956.
107
[166] I. Hutchinson, M. Chua, H.L. Browne, V. Trapani, T.D. Bradshaw, A.D. Westwell, M.F.G. Stevens, Antitumour benzothiazoles, Synthesis and in vitro biological properties of fluorinated 2-(4-aminophenyl)benzothiazoles, J. Med. Chem. 44 (2001) 1446-1455. [167] A. Grozav, L.I. Gaina, V. Pileczki, O. Crisan, L. Silaghi-Dumitrescu, B. Therrien, V. Zaharia, I. Berindan-Neagoe, The synthesis and antiproliferative activities of new arylidene-hydrazinyl-thiazole derivatives, Int. J. Mol. Sci. 15 (2014) 22059-22072. [168] K.M. Dawood, T.M.A. Eldebss, H.S.A El-Zahabi, M.H. Yousef, P. Metz, Synthesis of some new pyrazole-based 1,3-thiazoles and 1,3,4-thiadiazoles as anticancer agents, Eur. J. Med. Chem. 70 (2013) 740-749. [169] L. Mosula, B. Zimenkovsky, D. Havrylyuk, A. Missir, I.C. Chirita, R. Lesyk, Synthesis and antitumour activity of novel 2-thioxo-4-thiazolidinones with benzothiazole moieties, Farmacia 57(3) (2009) 321-330. [170] N.C. Desai, N. Bhatt, H. Somani, A. Trivedi, Synthesis, antimicrobial and cytotoxic activities of some novel thiazole clubbed 1,3,4-oxadiazoles, Eur. J. Med. Chem. 67 (2013) 54-59. [171] N. Zhua, Y. Ling, X. Lei, V. Handratta, A.M.H. Brodie, Novel P45017α inhibitors: 17-(2’oxazolyl)- and 17-(2’-thiazolyl)-androstene derivatives, Steroids 68 (2003) 603-611. [172] R.M. Mohareb, W.W. Wardakhan, G.A. Elmegeed, R.M.S. Ashour, Heterocyclizations of pregnenolone, Novel synthesis of thiosemicarbazone, thiophene, thiazole, thieno[2,3b]pyridine derivatives and their cytotoxicity evaluations, Steroids 77 (2012) 1560-1569. [173] R.M. Mohareb, F. Al-Omran, Reaction of pregnenolone with cyanoacetylhydrazine: Novel synthesis of hydrazide–hydrazone, pyrazole, pyridine, thiazole, thiophene derivatives and their cytotoxicity evaluations, Steroids 77 (2012) 1551-1559. [174] R.M. Mohareb, N.N.E. El-Sayed, M.A. Abdelaziz, Uses of cyanoacetylhydrazine in heterocyclic synthesis: Novel synthesis of pyrazole derivatives with anti-tumour activities, Molecules 17 (2012) 8449-8463. [175] R.M. Mohareb, D.H. Fleita, O.K. Sakka, Novel synthesis of hydrazide-hydrazone derivatives and their utilization in the synthesis of coumarin, pyridine, thiazole and thiophene derivatives with antitumour activity, Molecules 16 (2011) 16-27. [176] R.R.Reis, E.C. Azevedo, M.C.B.V. de Souza, V.F. Ferreira, R.C. Montenegro, A.J. Araujo, C. Pessoa, L.V. Costa-Lotufo, M.O. de Moraes, D.B.M. Jose Filho, A.M.T. de Souza, N.C.de Carvalho, H.C. Castro, C.R. Rodrigues, T.R.A. Vasconcelos, Synthesis and anticancer
activities
of
some
novel
2-(benzo[d]thiazol-2-yl)-8-substituted-2H-
pyrazolo[4,3-c]quinolin-3(5H)-ones, Eur. J. Med. Chem. 46 (2011) 1448-1452. 108
[177] R. Chaniyara, S.K. Tala, C. Chen, P. Lee, R. Kakadiya, H. Dong, B. Marvania, C. Chen, T. Chou, T. Lee, A. Shah, T. Su, Synthesis and antitumour evaluation of novel benzo[d]pyrrolo[2,1-b]thiazole derivatives, Eur. J. Med. Chem. 53 (2012) 28-40. [178] R. Romagnoli, P.G. Baraldi, C.L. Cara, M.K. Salvador, R. Bortolozzi, G. Basso, G. Viola, J. Balzarini, A. Brancale, X. Fu, J. Li, S. Zhang, E. Hamel, One-pot synthesis and biological evaluation of 2-pyrrolidinyl-4-amino-5-(3’,4’,5’ trimethoxy benzoyl)thiazole: A unique, highly active antimicrotubule agent, Eur. J. Med. Chem. 46 (2011) 6015-6024. [179] S.M. Rida, F.A. Ashour, S.A.M. El-Hawash, M.M. ElSemary, M.H. Badr, M.A. Shalaby, Synthesis of some novel benzoxazole derivatives as anticancer, anti-HIV-1 and antimicrobial agents, Eur. J. Med. Chem. 40 (2005) 949-959. [180] S. Bondock, S. Adel, H.A. Etman, F.A. Badria, Synthesis and antitumour evaluation of some new 1,3,4-oxadiazole-based heterocycles, Eur. J. Med. Chem. 48 (2012) 192-199. [181] S.I. Kovalenko, I.S. Nosulenko, A.Y. Voskoboynik, G.G. Berest, L.N. Antypenko, A.N. Antypenko, A.M. Katsev, Substituted 2-[(2-oxo-2H-[1,2,4]triazino[2,3-c]quinazolin-6yl)thio]acetamides with thiazole and thiadiazole fragments, Synthesis, physicochemical properties, cytotoxicity, and anticancer activity, Sci. Pharm. 80 (2012) 837-865. [182] S.A.F. Rostom, Synthesis and in vitro antitumour evaluation of some indeno [1,2-c]pyrazol(in)es substituted with sulfonamide, sulfonylurea(-thiourea) pharmacophores, and some derived thiazole ring systems, Bioorg. Med. Chem. 14 (2006) 6475-6485. [183] K.Z. Laczkowski, M. Switalska, A. Baranowska-Laczkowska, T. Plech, A. Paneth, K. Misiura, J. Wietrzyk, B. Czaplinska, A. Mrozek-Wilczkiewicz, K. Malarz, R. Musiol, I. Grela, Thiazole-based nitrogen mustards: Design, synthesis, spectroscopic studies, DFT calculation, molecular docking, and antiproliferative activity against selected human cancer cell lines, J. Mol. Structure 1119 (2016) 139-150. [184] S.A.F. Rostom, H.M. Faidallah, M.F. Radwan, M.H. Badr, Bifunctional ethyl 2-amino-4methylthiazole-5-carboxylate derivatives: Synthesis and in vitro biological evaluation as antimicrobial and anticancer agents, Eur. J. Med. Chem. 76 (2014) 170-181. [185] S.H.L.Kok, C.H. Chui, W. S. Lam, J. Chen, F.Y. Lau, R.S.M. Wong, G.Y.M. Cheng, P.Bo SanLai, T.W.T. Leung, M.W.Y. Yu, J.C. Tanga, A.S.ChiChan, Synthesis and structure evaluation of a novel cantharimide and its cytotoxicity on SK-Hep-1 hepatoma cells, Bioorg. Med. Chem. Lett. 17 (2007) 1155-1159. [186] W.X. Cai, A.L. Liu, Z.M. Li, W.L. Dong, X.H. Liu, N.B. Sun, Synthesis and anticancer activity of novel thiazole-5-carboxamide derivatives, Appl. Sci. 6(8) (2016) 1-10. 109
[187] X. Liu, L. Deng, H. Song, H. Jia, R. Wang, Asymmetric aza-mannich addition: Synthesis of modified chiral 2-(ethylthio)-thiazolone derivatives with anticancer potency, Org. Lett. 13(6) (2011) 1494-1497. [188] X. Zeng, B. Yin, Z. Hu, C. Liao, J. Liu, S. Li, Z. Li, M.C. Nicklaus, G. Zhou, S. Jiang, Total synthesis and biological evaluation of largazole and derivatives with promising selectivity for cancers cells, Org. Lett. 12(6) (2010) 1368-1371. [189] X.H. Shi, Z. Wang, Y. Xia, T.H. Ye, M. Deng, Y.Z. Xu, Y.Q. Wei, L. Yu, Synthesis and biological evaluation of novel benzothiazole-2-thiol derivatives as potential anticancer agents, Molecules 17 (2012) 3933-3944. [190] Y.N. Mabkhot, A. Barakat, A.M. Al-Majid, S. Alshahrani, S. Yousuf, M.I. Choudhary, Synthesis, reactions and biological activity of some new bis-heterocyclic ring compounds containing sulphur atom, Chem. Cent. J. 7(112) (2013) 1-9. [191] Y.X. Li, X. Zhai, W.K. Liao, W.F. Zhu, Y. He, P. Gong, Design, synthesis and biological evaluation of new rhodacyanine analogues as potential antitumour agents, Chin. Chem. Lett. 23 (2012) 415-418. [192] Y. Luo, F. Xiao, S. Qian, W. Lu, B. Yang, Synthesis and in vitro cytotoxic evaluation of some thiazolylbenzimidazole derivatives, Eur. J. Med. Chem. 46 (2011) 417-422. [193] Y. Matsuya, T. Kawaguchi, K. Ishihara, K. Ahmed, Q. Zhao, T. Kondo, H. Nemoto, Synthesis of macrosphelides with a thiazole side chain, New antitumour candidates having apoptosis-inducing property, Org. Lett. 20(6) (2006) 4609-4612. [194] Y. Kanda, T. Ashizawa, K. Kawashima, S. Ikeda, T. Tamaoki, Synthesis and antitumour activity of novel C-8 ester derivatives of leinamycin, Bioorg. Med. Chem. Lett. 13 (2013) 455-458. [195] M. Chakrabarty, T. Kundu, S. Arima, Y. Harigaya, An expedient, regioselective synthesis of novel 2-alkylamino- and 2-alkylthiothiazolo[5,4-e]- and -[4,5-g]indazoles and their anticancer potential, Tetrahedron 64 (2008) 6711-6723. [196] M.V. de Oliveira Cardoso, D.R.M. Moreira, G.B. Oliveira Filhoa, S.M.T. Cavalcanti, L.C.D. Coelho, J.W.P. Espindol, L.R. Gonzalez, M.M. Rabello, M.Z. Hernandes, P.M.P. Ferreira, C. Pessoad, C.A. de Simonee, E.T. Guimarae, M.B.P. Soares, A.C. LimaLeite, Design, synthesis and structure-activity relationship of phthalimides endowed with dual antiproliferative and immunomodulatory activities, Eur. J. Med. Chem. 96 (2015) 491503.
110
[197] M.I.L. Soares, A.F. Brito, M. Laranjo, A.M. Abrantes, M.F. Botelho, J.A. Paixao, A.M. Beja, M.R. Silva, M.V.D. Teresa, P. Melo, Chiral 6-hydroxymethyl-1H,3H-pyrrolo[1,2c]thiazoles: Novel antitumour DNA monoalkylating agents, Eur. J. Med. Chem. 45 (2010) 4676-4681. [198] A. Carbone, B. Parrino, G.V. Vita, A. Attanzio, V. Spano, A. Montalbano, P. Barraja, L. Tesoriere, M.A. Livrea, P. Diana, G. Cirrincione, Synthesis and antiproliferative activity of thiazolyl-bis-pyrrolo[2,3-b]pyridines and indolyl-thiazolyl-pyrrolo[2,3-c]pyridines, nortopsentin analogues, Mar. Drugs 13 (2015) 460-492. [199] B. Parrino, A. Carbone, G.D. Vita, C. Ciancimino, A. Attanzio, V. Spano, A. Montalbano, P. Barraja, L. Tesoriere, M.A. Livrea, P. Diana, G. Cirrincione, 3-[4-(1H-Indol-3-yl)-1,3thiazol-2-yl]-1H-pyrrolo[2,3-b]pyridines, nortopsentin analogues with antiproliferative activity, Mar. Drugs 13 (2015) 1901-1924. [200] R. Sadashiva, D. Naral, J. Kudva, S.M. Kumar, K. Byrappa, M.R. Shafeeulla, M. Kumsi, Synthesis, structure characterization, in vitro and in silico biological evaluation of a new series of thiazole nucleus integrated with pyrazoline scaffolds, J. Mol. Structure 1145 (2017) 18-31. [201] S. Mirza, S.A. Naqvi, K.M. Khan, U. Salar, M.I. Choudhary, Facile synthesis of novel substituted aryl-thiazole (SAT) analogs via onepot multi-component reaction as potent cytotoxic agents against cancer cell lines, Bioorg. Chem. 70 (2017) 133-143. [202] M. Popsavin, S. Spaic, M. Svircev, V. Kojic, G. Bogdanovic, V. Popsavina, Synthesis and antitumour activity of new tiazofurin analogues bearing a 2,3-anhydro functionality in the furanose ring, Bioorg. Med. Chem. Lett. 17 (2007) 4123-4127. [203] M.A. Abdelgawad, A. Belal, O.M. Ahmed, Synthesis, molecular docking studies and cytotoxic screening of certain novel thiazolidinone derivatives substituted with benzothiazole or benzoxazole, J. Chem. Pharm. Res. 5(2) (2013) 318-327. [204] H. He, X. Wang, L. Shi, W. Yin, Z. Yang, H. He, Y. Liang, Synthesis, antitumour activity and mechanism of action of novel 1,3-thiazole derivatives containing hydrazide-hydrazone and carboxamide moiety, Bioorg. Med. Chem. Lett. 26 (2016) 3263-3270. [205] S.M. Gomha, K.D. Khalil, A convenient ultrasound-promoted synthesis of some new thiazole derivatives bearing a coumarin nucleus and their cytotoxic activity, Molecules 17 (2012) 9335-9347. [206] S.M. Gomha, S.A. Ahmed, A.O. Abdelhamid, Synthesis and cytotoxicity evaluation of some novel thiazoles, thiadiazoles, and pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidin5(1H)-ones incorporating triazole moiety, Molecules 20 (2015) 1357-1376. 111
[207] S.M. Gomha, Y.H. Zaki, A.O. Abdelhamid, Utility of 3-acetyl-6-bromo-2H-chromen-2one for the synthesis of new heterocycles as potential antiproliferative agents, Molecules 20 (2015) 21826-21839. [208] S.M. Gomha, T.A. Salaheldin, H.M.E. Hassaneen, H.M. Abdel-Aziz, M.A. Khedr, Synthesis, characterization and molecular docking of novel bioactive thiazolyl-thiazole derivatives as promising cytotoxic antitumour drug, Molecules 21(3) (2016) 1-17. [209] M.M. Ghorab, D.A.A. El Ella, H.I. Heiba, A.M. Soliman, Synthesis of certain new thiazole derivatives bearing a sulfonamide moiety with expected anticancer and radiosensitizing activities, J. Materials Sci. Eng. A1 (2011) 684-691. [210] M.M. Ramla, M.A. Omar, H. Tokuda, H. El-Diwania, Synthesis and inhibitory activity of new benzimidazole derivatives against Burkitt’s lymphoma promotion, Bioorg. Med. Chem. 15 (2007) 6489-6496. [211] V. Gududuru, E. Hurh, J.T. Dalton, D.D. Miller, Synthesis and antiproliferative activity of 2-aryl-4-oxo-thiazolidin-3-yl-amides for prostate cancer, Bioorg. Med. Chem. Lett. 14 (2004) 5289-5293. [212] T. Tzanova, M. Gerova, O. Petrov, M. Karaivanova, D. Bagrel, Synthesis and antioxidant potential of novel synthetic benzophenone analogues, Eur. J. Med. Chem. 44 (2009) 27242730. [213] K. Saravanan, R. Elancheran, S. Divakar, S.A.A. Anand, M. Ramanathan, J. Kotoky, N.K. Lokanath, S. Kabilan, Design, synthesis and biological evaluation of 2-(4-phenylthiazol-2yl) isoindoline-1,3-dione derivatives as anti-prostate cancer agents, Bioorg. Med. Chem. Lett. 27 (2017) 1199-1204. [214] M.M. Ghorab, M.S. Alsaid, A.A. Shahat, Synthesis of some sulfonamide incorporating enaminone,
quinolone
moieties
and
thiazoloquinazoline
derivative
induce
the
cytoprotective enzyme NAD(P)H: Quinone oxidoreductase, Biomed. Res. 27(3) (2016) 695-701. [215] F.S.A. Rahman, S.K. Yusufzai, H. Osman, D. Mohamad, Synthesis, characterisation and cytotoxicity activity of thiazole substitution of coumarin derivatives (characterisation of coumarin derivatives), J. Physical Sci. 27(1) (2016) 77-87. [216] V. Pejchal, S. Stepankova, M. Pejchalova, K. Kralovec, R. Havelek, Z. Ruzickova, H. Ajani, R. Lo, M. Lepsik, Synthesis, structural characterization, docking, lipophilicity and cytotoxicity of 1-[(1R)-1-(6-fluoro-1,3-benzothiazol-2-yl)ethyl]-3-alkyl carbamates, novel acetylcholinesterase and butyrylcholinesterase pseudo-irreversible inhibitors, Bioorg. Med. Chem. 24 (2016) 1560-1572. 112
[217] A. Grozav, O. Balacescu, L. Balacescu, T. Cheminel, I. Berindan-Neagoe, B. Therrien, Synthesis, anticancer activity, and genome profiling of thiazolo arene ruthenium complexes, J. Med. Chem. 58 (2015) 8475-8490. [218] K.Z. Laczkowski, M. Switalska, A. Baranowska-Lczkowska, T. Plech, A. Paneth, K. Misiura, J. Wietrzyk, B. Czaplinska, A. Mrozek-Wilczkiewicz, K. Malarz, R. Musioł, I. Grela, Thiazole-based nitrogen mustards: Design, synthesis, spectroscopic studies, DFT calculation, molecular docking, and antiproliferative activity against selected human cancer cell lines, J. Mol. Structure 1119 (2016) 139-150. [219] Z.L. Wu, Y.L. Fang, Y.T. Tang, M.W. Xiao, J. Ye, G.X. Lia, A.X. Hu, Synthesis and antitumour evaluation of 5-(benzo[d][1,3]dioxol-5-ylmethyl)-4-(tert-butyl)-N-arylthiazol2-amines, Med. Chem. Comm. 7 (2016) 1768-1774. [220] L. Balanean, C. Braicu, I. Berindan-Neagoe, C. Nastasa, B. Tiperciuc, P. Verite, O. Oniga, Synthesis of novel 2-metylamino-4-substituted-1,3-thiazoles with antiproliferative activity, Rev. Chim. 65(12) (2014) 1413-1417. [221] K.K. Bansal, D. Sharma, A. Sharma, H. Rajak, P.C. Sharma, Novel thiazole clubbed triazole derivatives as antimicrobial, antimalarial and cytotoxic agents. Indian J. Heterocycl. Chem. 28(2) (2018) 305-312. [222] P. Sharma, T.S. Reddy, D. Thummuri, K.R. Senwar, N.P. Kumar, V.G.M. Naidu, S.K. Bhargava, N. Shankaraiah, Synthesis and biological evaluation of new benzimidazolethiazolidinedione hybrids as potential cytotoxic and apoptosis inducing agents, Eur. J. Med. Chem. 124 (2016) 608-621. [223] F. Tay, C. Erkan, N.Y. Sariozlu, E. Ergene, S. Demirayak, Synthesis, antimicrobial and anticancer activities of some naphthylthiazolylamine derivatives, Biomed. Res. 28(6) (2017) 2696-2703. [224] S.M. Gomha, N.A. Kheder, M.R. Abdelaziz, Y.N. Mabkhot, A.M. Alhajoj, A facile synthesis and anticancer activity of some novel thiazoles carrying 1,3,4-thiadiazole moiety, Chem. Cent. J. 11 (2017) 25. [225] J. Park, M.I. El-Gamal, Y.S. Lee, C. Oh, New imidazo[2,1-b]thiazole derivatives: Synthesis, in vitro anticancer evaluation, and in silico studies, Eur. J. Med. Chem. 46 (2011) 5769-5777. [226] J. Park, C. Oh, Synthesis of new 6-(4-fluorophenyl)-5-(2-substituted pyrimidin-4-yl) imidazo [2, 1-b] thiazole derivatives and their antiproliferative activity against melanoma cell line, Bull. Korean Chem. Soc. 31(10) (2010) 2854-2860.
113
[227] Y. Liang, Z. Yue, J. Li, C. Tan, Z. Miao, W. Tan, C. Yang, Natural product-based design, synthesis and biological evaluation of anthra[2,1-d]thiazole-6,11-dione derivatives from rhein as novel antitumour agents, Eur. J. Med. Chem. 84 (2014) 505-515. [228] K. Santos, M. Laranjo, A.M. Abrantes, A.F. Brito, C. Gonçalves, A.B.S. Ribeiro, F.M. Botelho, M.I.L. Soares, A.S.R. Oliveira, T. Pinho Melo, Targeting triple-negative breast cancer cells with 6,7-bis(hydroxymethyl)-1H,3H-pyrrolo[1,2-c]thiazoles, Eur. J. Med. Chem. 79 (2014) 273-281. [229] V. Zaharia, A. Ignat, N. Palibroda, B. Ngameni, V Kuete, C.N. Fokunang, M.L. Moungang, B.T. Ngadjui, Synthesis of some p-toluenesulfonyl-hydrazinothiazoles and hydrazino-bisthiazoles and their anticancer activity, Eur. J. Med. Chem. 45 (2010) 50805085. [230] L. Shao, X. Zhou, Y. Hu, Z. Jin, J. Liu, J. Fang, Synthesis and evaluation of novel ferrocenyl thiazole derivatives as anticancer agents. Synthesis and Reactivity in Inorganic, Metal-Organic and Nano-Metal Chem. 36 (2006) 325-330. [231] G. Sadhasivam, K. Kulanthai, A. Natarajan, Synthesis and anti-cancer studies of 2, 6disubstituted benzothiazole derivatives, Orient. J. Chem. 31(2) (2015) 819-826. [232] M.D. Altintop, A. Ozdemir, G. Turan-Zitouni, S. Ilgin, O. Atli, R. Demirel, Z.A. Kaplancikli, A novel series of thiazolyl-pyrazoline derivatives: Synthesis and evaluation of antifungal activity, cytotoxicity and genotoxicity, Eur. J. Med. Chem. 92 (2015) 342352. [233] M.J. Gorczynski, R.M. Leal, S.L. Mooberry, J.H. Bushwellera, M.L. Browna, Synthesis and evaluation of substituted 4-aryloxy- and 4-arylsulfanyl-phenyl-2-aminothiazoles as inhibitors of human breast cancer cell proliferation, Bioorg. Med. Chem. 12 (2004) 10291036. [234] A. Andreani, S. Burnelli, M. Granaiola, A. Leoni, A. Locatelli, R. Morigi, M. Rambaldi, L. Varoli, N. Calonghi, C. Cappadone, G. Farruggia, M. Zini, C. Stefanelli, L. Masotti, N. S. Radin, R.H. Shoemaker, New antitumour imidazo[2,1-b]thiazole guanylhydrazones and analogues, J. Med. Chem. 51(4) (2008) 809-816. [235] A. Andreani, M. Granaiola, A. Leoni, A. Locatelli, R. Morigi, M. Rambaldi, G. Lenaz, R. Fato, C. Bergamini, G. Farruggia, Potential antitumour agents. 37. Synthesis and antitumour activity of guanylhydrazones from imidazo[2,1-b]thiazoles and from the new heterocyclic system thiazolo[2‘,3‘:2,3]imidazo[4,5-c]quinolone, J. Med. Chem. 48(8) (2005) 3085-3089.
114
[236] M. Popsavin, L. Torovic, M. Svircev, V. Kojic, G. Bogdanovic, V. Popsavina, Synthesis and antiproliferative activity of two new tiazofurin analogues with 20-amido functionalities, Bioorg. Med. Chem. Lett. 16 (2006) 2773-2776. [237] S.M. Gomha, A.O. Abdelhamid, N.A. Abdelrehem, S.M. Kandeel, Efficient synthesis of new benzofuran-based thiazoles and investigation of their cytotoxic activity against human breast carcinoma cell lines, J. Heterocycl. Chem. 55(4) 2018 995-1001. [238] S.M. Gomha, M.R. Abdelaziz, N.A. Kheder, H.M. Abdel-Aziz, S. Alterary, Y.N. Mabkhot, A facile access and evaluation of some novel thiazole and 1, 3, 4-thiadiazole derivatives incorporating thiazole moiety as potent anticancer agents, Chem. Cent. J. 11(1) (2017) 105. [239] T.D. Dos Santos Silva, L.M. Bomfim, A.C.B. da Cruz Rodrigues, R.B. Dias, C.B.S. Sales, C.A.G. Rocha, M.B.P. Soares, D.P. Bezerra, M.V. de Oliveira Cardoso, A.C.L. Leite, G.C.G. Militao, Anti-liver cancer activity in vitro and in vivo induced by 2-pyridyl 2, 3thiazole derivatives, Toxicol. Appl. Pharmacol. 329 (2017) 212-223. [240] P.K.N. Sarangi, J. Sahoob, S. Beherac, S.K. Paidesetty, G.P. Mohantae, Cytotoxic investigation of some newly synthesized quinoline-thiazole based azo compounds, Indian J. Chem. 56B (2017) 1256-1264. [241] R. Xu, Y. Tian, S. Huang, J. Yu, Y. Deng, M. Zhan, T. Zhang, F. Wang, L. Zhao, Y. Chen, Synthesis and evaluation of novel thiazole-based derivatives as selective inhibitors of DNA-binding domain of the androgen receptor, Chem. Biol. Drug Des. 91(1) (2018) 172-180. [242] E. Abdel-Latif, E.M. Keshk, A. Saeed, A.M. Khalil, Synthesis and anticancer evaluation of some new heterocyclic scaffolds incorporating the acetanilide moiety, Modern Org. Chem. Res. 2(3) (2017) 112-123. [243] R.M. Mohareb, A.E.M. Abdallah, A.A. Mohamed, Synthesis of novel thiophene, thiazole and coumarin derivatives based on benzimidazole nucleus and their cytotoxicity and toxicity evaluations, Chem. Pharm. Bull. 66 (2018) 309-318. [244] A. Ahamed, I.A. Arif, M. Mateen, R.S. Kumar, A. Idhayadhulla, Antimicrobial, anticoagulant, and cytotoxic evaluation of multidrug resistance of new 1,4dihydropyridine derivatives, Saudi J. Biol. Sci. 25(6) (2018) 1227-1235. [245] S.M. Gomha, M.M. Edrees, F.M.A. Altalbawy, Synthesis and characterization of some new bis-pyrazolyl-thiazoles incorporating the thiophene moiety as potent anti-tumour agents, Int. J. Mol. Sci. 17 (2016) 1499.
115
[246] C. Ge, L. Chang, Y. Zhao, C. Chang, X. Xu, H. He, Y. Wang, F. Dai, S. Xie, C. Wang, Design, synthesis and evaluation of naphthalimide derivatives as potential anticancer agents for hepatocellular carcinoma, Molecules 22 (2017) 342. [247] M.P. Tantak, J. Wang, R.P. Singh, A. Kumar, K. Shah, D. Kumar, 2-(3’-Indolyl)-Narylthiazole-4-carboxamides: Synthesis and evaluation of antibacterial and anticancer activities, Bioorg. Med. Chem. Lett. 25 (2015) 4225-4231. [248] K. Vaarla, R.K. Kesharwani, K. Santosh, R.R. Vedula, S. Kotamraju, M.K. Toopurani, Synthesis, biological activity evaluation and molecular docking studies of novel coumarin substituted thiazolyl-3-aryl-pyrazole-4-carbaldehydes, Bioorg. Med. Chem. Lett. 25 (2015) 5797-5803. [249] A. Leoni, A. Locatelli, R. Morigi, M. Rambaldi, Novel thiazole derivatives: A patent review (2008-2012. Part 2), Expert Opin. Ther. Pat. 24(7) (2014) 759-777. [250] P. Mei, S. Kun, L. Ying, H. Aixi, Application of 5-(2-nitro ethyl) thiazole derivatives as anticancer drug, CN105078977, A, November 25, 2015. [251] G. Wang, Q. Jiang, Q. Zhong, Q. Zhang, S. Zheng, Anti-migration and anti-invasion thiazole analogs for treatment of cellular proliferative disease, US 20150274714 A1, October 1, 2015. [252] S. Han, Y.S. Kim, J.T. Hong, N. Nam, D.N. Mai, D.T. Phuong, O.T. Kim, Novel phenylthiazole-based hydroxamic acid and anti-cancer composition containing same as active ingredient, WO2015016442, A1, February 5, 2015. [253] J. Lajeunesse, J.D. DiMarco, E. Brunswick, M. Galella, R. Chidambaram, Process for preparing 2-aminothiazole-5-aromatic carboxamides as kinase inhibitors, US 8,680,103 B2, March 25, 2014. [254] M. Dumble, T. Gilmer, R. Kumar, P.F. LeboWitz, S.R. Morris, S. Laquerre, Combination of a B-RAF inhibitor: N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol4-yl]-2fluorophenyl}2,6-difluorobenzenesulfonamide and the Akt inhibitor: N-{(1s)-2 amino-1-[(3- fluorophenyl) methyl]ethyl}-5-chioro-4-(4-chioro 1-methyl-1H-pyrazol-syl)-2-10 thiophenecarboxamide useful in the treatment of cancer, US 8,796,298 B2, August 5, 2014. [255] M. Mortimore, J. Golec, C. Davis, D. Robinson, J. Studley, Thiazoles and pyrazoles useful as kinase inhibitors, US 8,785,444 B2, July 22, 2014. [256] P.P. Beroza, K.V. Damodaran, E. Laborde, W. Thomas, Substituted thiazoles as VEGFR2 kinase inhibitors, US 2013/0184280 A1, July 18, 2013.
116
[257]
J. Song, Method of cancer treatment with 2-(1H-indole-3-carbonyl)-thiazole-4 carboxylic acid methyl ester, US 2013/0338201 A1, December 19, 2013.
[258] G. W. Shipps, M. Richards, C.C. Cheng, X. Huang, Thiazole carboxamide derivatives and their use to treat cancer, US 8,394,960 B2, March 12, 2013. [259] K. Uoto, Y. Sugimoto, H. Naito, M. Mlyazaki, K. Yoshida, M. Aonuma, Imidazothiazole derivatives having proline ring structure, US 8,404,691 B2, March 26, 2013. [260]
T. Irie, M. Sawa, S. Ito, C. Tanaka, S.G. Ro, H.C. Park, Thiazolidinone derivatives, US 8,119,812, B2, February 21, 2012.
[261] A. Hamed, B. Christoph, B. Christine, G. Markus, G. John, S. Romain, S. Thierry, T.W. Jodi, Thiazolidin-4-one and [1,3]-thiazinan-4-one compounds as orexin receptor antagonists, US 2012/0088759 A1, April 12, 2012. [262] H. An, B. Xi, Y. Abassi, X. Wang, X. Xiao, Imidazothiazole-chalcone derivatives as potential heterocyclic compounds and uses as anticancer agents, US 8,252,822 B2, August 28, 2012. [263] M. Mortimore, J. Golec, C. Davis, D. Robinson, J. Studley, Thiazoles and pyrazoles useful as kinase inhibitors, US 8,268,811 B2, September 18, 2012. [264] T. Irie, M. Sawa, S. Ito, C. Tanaka, S.G. Ro, H.C. Park, Thiazolidinone derivatives, U.S. Patent US 0190299, A1, August 4, 2011. [265] M.P. Mortimore, C.J. Davis, J.M.C. Golec, J. Studley, D.D. Robinson, Thiazoles and pyrazoles useful as kinase inhibitors, US 2011/0060013 A1, March 10, 2011. [266] D. Romo, J. Liu, N.S. Choi, Z. Shi, W. Low, Y. Dang, T. Schneider-Poetsch, Anticancer agents and use, US 7,737,134 B2, June 15, 2010. [267] D.D. Miller, J.T. Dalton, V. Gududuru, E. Hurh, (4R)-2-(4-methoxyphenyl)-Noctadecylthiazolidine-4-carboxamide; Antiacarcinogenic agent for destroying a melanoma cell, US 7,662,842, B2, February 16, 2010. [268] J. Lajeunesse, J.D. DiMarco, M. Galella, R. Chidambaram, Process for preparing 2aminothiazole-5-aromatic carboxamides as kinase inhibitors, US 7,491,725 B2, February 17, 2009. [269] C. Mara, C. Gennaro, D.M. Sergio, G. Mario, Use of thiazolidinone derivatives as antiangiogenic agents, US 0261980, A1, October 23, 2008. [270] S.M. Courtney, P.A. Hay, D.I.C. Scopes, Novel furanthiazole derivatives which are useful as inhibitors of heparanase, US 7,326,727 B2, February 5, 2008. [271] G. Siemeister, H. Briem, V. Schulze, K. Eis, L. Wortmann, W. Schwede, H. Schneider, V. Eberspaecher, H.H. Stumpp, Inhibitors of polo-like kinases; (4,4-dimethyl-4,5-dihydro117
oxazol-2-yl)-[3-ethyl-4-oxo-5-[1-[3-(2-pyrrolidin-1-yl-ethyl)-phenylamino]-meth-(E/Z)ylidene]-thiazolidin-(2-(E or Z))-ylidene]-acetonitrile; cancer, auto-immune diseases, cardiovascular diseases, US 0037862, A1, February 15, 2007. [272] B. Lippa, Mystic, A. Kwan, J. Morris, S.D. LaGreca, M.D. Wessel, Novel isothiazole derivatives that are useful in the treatment of hyperproliferative diseases, US 7,276,602 B2, October 2, 2007. [273] W. SchWede, V. Schulze, K. Eis, B. Buchmann, H. Briem, G. Siemeister, U. Boemer, K. Parczyk, Thiazolidinones and the use therof as polo-like kinase inhibitors, US 0079503, A1, April 13, 2006. [274] M. Pfahl, C. Tachdjian, T.R. Wiemann, N.C. Christopher, L.W. Spruce, A.F. Giachino, A.A. Kaspar, J.W. Zapf. Benzoxazole, benzothiazole, and benzimidazole derivatives for the treatment of cancer and other diseases, US 2005/0014767 A1, January 20, 2005. [275] E.W. Yue, Novel 3-(2, 4 dimethylthiazol-5-yl)indeno[1,2-c]pyrazol-4-one derivatives which are useful as cyclin dependent kinase (Cdk) inhibitors, US 6,706,718 B2, March 16, 2004. [276] J.J.V. Duncia, D.S. Gardner, J.O.B Santella, N-adamant-1-y1-N1-[4 chlorobenzothiazol-2y1] urea useful in the treatment of inflammation and as an anticancer radiosensitizing agent, US 6,214,851 B1, April 10, 2001. [277] E. Albert, E. Bacque, C. Nemecek, A. Ugolini, S. Wentzler, 6-Triazolopyridazine sulfanyl benzothiazole derivatives as MET inhibitors, US 9,321,777 B2, April 26, 2016. [278] R. Roziev, A. Goncharova, K.T. Erimbetov, V. Podgorodnichenko, V. Khomichenok, N. Novozhilova, Agent for the prophylaxis and/or treatment of neoplastic diseases, US 20160038472, A1. February 11, 2016. [279] R.J. Boohaker, M.W. Lee, P. Vishnubhotla, J.M. Perez, A.R. Khaled. The use of therapeutic peptides to target and to kill cancer cells, Curr. Med. Chem. 19(22) (2012) 3794-3804. [280] Y. Xiao, M. Jie, B. Li, C. Hu, R. Xie, B. Tang, S. Yang. Peptide-based treatment: A promising cancer therapy. J. Immun. Res. (2015) 1-13 Article ID 761820. [281] J. Thompson, E. Cundliffe, M.J.R. Stark, The mode of action of berninamycin and the mechanism of resistance in the producing organism, Streptomyces bernensis, J. Gen. Microb. 128 (1982) 815-884. [282] A. Ninomiya, S. Kodani, Isolation and identification of berninamycin A from Streptomyces atroolivaceus, NPAIJ. 7(4) (2011) 163-167.
118
[283] E. Cundliffe, J. Thompson, Concerning the mode of action of micrococcin upon bacterial protein synthesis, Eur. J. Biochem. 118 (1981) 47-52. [284] X. Just-Baringo, F. Albericio, M. Alvarez, Thiopeptide antibiotics: retrospective and recent advances, Mar. Drugs 12 (2014) 317-351. [285] https://www.google.com/patents/WO2002102400A1?cl=en [accessed on 14.05.2017] [286] L.C.W. Brown, M.G. Acker, J. Clardy, C.T. Walsh, M.A. Fischbach, Thirteen posttranslational modifications convert a 14-residue peptide into the antibiotic thiocillin, PNAS. 106(8) (2009) 2549-2553. [287] S. Kim, Use of macrocyclic peptide compound as anticancer agents and method for diagnosing cancer, Patent WO 2002102400 A1, June 14, 2002. [288] http://www.google.ch/patents/WO2002066046A1?cl=en. [accessed on 14.05.2017].
119
Highlights: •
Drugs containing 1,3-thiazole scaffold are having clinical applications in anticancer drug therapies.
•
Diverse biological targets and their potent inhibitors related to anticancer actions of thiazoles have been described.
•
Thiazole-containing compounds are important in enzyme inhibition including enzyme-linked receptors located on the cell membrane and the cell cycle.
•
A large number of compounds were cytotoxic against several cancer cell lines.
•
Brief summary of recent patents and novel cyclic peptide antibiotics in cancer treatment has been provided.
Declaration of interests √ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Authors declare no conflict of interest. The authors alone are responsible for the content and writing of the paper.