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pyrazoline–thiazolidine-based hybrids
Accepted Manuscript Synthetic Approaches, Structure Activity Relationship and Biological Applications for Pharmacologically Attractive Pyrazole/Pyrazoline-Thiazolidine-Based Hybrids Dmytro Havrylyuk, Olexandra Roman, Roman Lesyk PII:
S0223-5234(16)30110-6
DOI:
10.1016/j.ejmech.2016.02.030
Reference:
EJMECH 8381
To appear in:
European Journal of Medicinal Chemistry
Received Date: 12 December 2015 Revised Date:
10 February 2016
Accepted Date: 11 February 2016
Please cite this article as: D. Havrylyuk, O. Roman, R. Lesyk, Synthetic Approaches, Structure Activity Relationship and Biological Applications for Pharmacologically Attractive Pyrazole/PyrazolineThiazolidine-Based Hybrids, European Journal of Medicinal Chemistry (2016), doi: 10.1016/ j.ejmech.2016.02.030. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. 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.
ACCEPTED MANUSCRIPT
Synthetic Approaches, Structure Activity Relationship and Biological Applications for Pharmacologically Attractive Pyrazole/Pyrazoline-Thiazolidine-Based Hybrids
N
Hybridization
H N
X
O ACTIVITY ANTITUMOR S
S O
N
N
3 ANTIMICROBIAL ACTIVITY R O
SC
N H
S
ANTIFUNGAL ACTIVITY N
N
H N
N H
S N
Hybridization
AC C
EP
TE D
N H
ANTIINFLAMMATORY ACTIVITY O 1 Ar N ANTIPARASITIC ACTIVITY N ANTIVIRAL ACTIVITY 2 Ar
M AN U
O
RI PT
Dmytro Havrylyuk, Olexandra Roman & Roman Lesyk
ACCEPTED MANUSCRIPT
Synthetic Approaches, Structure Activity Relationship and Biological Applications for Pharmacologically Attractive Pyrazole/Pyrazoline-Thiazolidine-Based Hybrids
Dmytro Havrylyuka,b, Olexandra Romana & Roman Lesyka,* a
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Department of Pharmaceutical, Organic and Bioorganic Chemistry
Danylo Halytsky Lviv National Medical University, 69 Pekarska Street, Lviv, 79010, Ukraine Department of Chemistry, University of Kentucky,
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505 Rose Street, Lexington, Kentucky 40506, United States
SC
b
*
corresponding author
[email protected], [email protected] (Roman Lesyk) tel. +38 0322 75-59-66
AC C
EP
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fax. +38 0322 75-77-34
ACCEPTED MANUSCRIPT
Abstract: The features of the chemistry of 4-thiazolidinone and pyrazole/pyrazolines as pharmacologically attractive scaffolds were described in a number of reviews in which the main approaches to the synthesis of mentioned heterocycles and their biological activity were analyzed. However, the pyrazole/pyrazoline-thiazolidine-based hybrids as biologically active compounds is
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poorly discussed in the context of pharmacophore hybrid approach. Therefore, the purpose of this review is to summarize the data about the synthesis and modification of heterocyclic systems with thiazolidine and pyrazoline or pyrazole fragments in molecules as promising objects of modern
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analysis and mechanistic insights of mentioned hybrids.
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bioorganic and medicinal chemistry. The description of biological activity was focused on SAR
AC C
EP
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Keywords: synthesis, biological activity, pyrazole, pyrazoline, thiazolidine.
ACCEPTED MANUSCRIPT
1. Introduction
Pharmacophore hybrid approach is a current concept in drug design and development to produce molecules with improved affinity and efficacy. There are some reviews dealing with the concept of molecular hybridization and the promises/challenges associated with these hybrid
RI PT
molecules along with recent advances on anticancer hybrids [1-3]. Various heteroaryl based hybrids in particular isatin and coumarins [3] or indoline-thiazolidinones [4] have been recently reviewed as conjugates with remarkable inhibitory potential.
SC
Design of new drug-like small molecules based on the pharmacologically attractive scaffolds of thiazolidine (4-thiazolidinone) [5-10] and pyrazole or pyrazoline [11-15] is a
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reasonable and promising direction in modern medicinal chemistry. The chemical approaches for the synthesis of thiazolidinone- and pyrazole-based derivatives and their pharmacological activity were described in a numerous reviews [5-12]. However, the pyrazole/pyrazoline-thiazolidine-based conjugates as biologically active compounds are poorly reviewed in the context of pharmacophore hybrid approach.
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The recent synthetic studies of pyrazole-thiazolidines and related hybrids and biological investigations for their antitumor, antimicrobial, antiviral, antiparasitic, anti-inflammatory activities to
identify
the
promising
drug-like
compounds.
Thus,
the
pyrazole-
EP
allowed
thiazolidinones/thiazoles have been patented as inhibitors of necroptosis [16], VHR protein tyrosine
AC C
phosphatase inhibitors [17], Pin1-modulating compounds [18], compounds for modulating RNAbinding proteins [19] and activators of pro-apoptotic BAX [20]. In addition, the pyrazolethiazolidinone hybrids have been studied for their possibility to inhibit the TNF-α–TNFRc1 interaction [21], as inhibitors of histone acetyltransferases [22] and inhibitors of COX [31, 39] and ADAMTS-5 enzymes [83]. Therefore, the purpose of this review is to summarize the data about the synthesis and biological activity of heterocyclic systems with thiazolidine and pyrazole/pyrazoline fragments in molecules. The most promising pyrazole-thiazolidinone/thiazole hybrids and target heterocycles that have been reviewed as fragments of hybrid molecules are depicted in the Figure 1.
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O
Hybridization
F
Pyraz
Thiaz O
N S
O
O
H N
S
S
N H
N H
S
RNA binding proteins modulator [19]
N
Ph
N
O F
Ph
F F
O
N
S
Ph
N
S S
N N CH3
VHR protein tyrosine phosphatase inhibitor [17]
N
CH3
TNF-a inhibitor [21]
O
N N Ph
O
S
N
(CH2)nCOOH
S
SC
N
S
Pro-apoptotic BAX activator [20]
O
S
N
N H
RI PT
MeO
N
N
N H
S
N
S
CH3
O
Necroptosis inhibitor [16]
NH
CH3
H3C
N
N
N
NH
N H
N S
N
N N
N
H3C
n = 3: Pin1-modulator [18] n = 5: HAT-inhibitor [22]
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Figure 1. Heterocycles for pyrazole/pyrazoline-thiazole/thiazolidine hybridization and the most promising conjugates.
The reviewed hybrids were classified as 2-, 3- and 5-pyrazole/pyrazoline-substituted
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thiazolidines based on linkage of target heterocyclic cores. The basic approaches for the synthesis of mentioned derivatives provide a combination of two “small” molecules in aminolysis reactions, acylation and Knoevenagel procedure or heterocyclization of monocyclic compounds via the [2+3]-
EP
cyclization reaction yielding the series of non-condensed bicyclic systems.
AC C
2. Synthetic approaches for 4-thiazolidinone-based hybrids with pyrazole/pyrazoline fragments in position 2.
Detailed biological activity evaluation of pyrazoline-thiazolidinone conjugates 1.2-1.7 and pyrazoline-thiazoles 1.8, 1.9 (Figure 2), synthesized via the [2+3]-cyclocondensation of 4,5dihydropyrazole-1-carbothioamides 1.1 as S,N-binucleophiles in reactions with equivalents of dielectrophilic synthon [C2]2+, allowed to identify compounds with antimicrobial [23-28], antiviral [29, 30], anti-inflammatory [31], antitumor [32-35] and insecticidal [36] activities. For synthesis of target derivatives α-halogenocarboxylic acids [31, 33] and their ethyl esters [23-29, 35, 36], maleic
ACCEPTED MANUSCRIPT
anhydride [30], maleimides [30, 38], β-aroylacrylic acids [30], dimethyl acetylenedicarboxylate [37], bromoacetophenones [23, 24, 28, 29, 35] and ethyl 4-chloroacetoacetate [35] were used as equivalents of dielectrophilic synthon [C2]2+. O
O
N N
R
O
N N
1.3 [30]
O
O
O
Ar O
R
N S
O
1.2 [23-29, 31, 33, 35, 36]
1.1 NH2
Br
O
MeO
2
Ar
N
R
N
N
1
R
O Ar O
N N
2
N
S
R
1
O
OMe
1
1.7 [37]
1.8 [35]
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R 1.9 [23, 24, 28, 29, 35]
O
S
O
O
S
S
R
1
OMe
R
N
N
1.6 [30]
OEt OEt
N
N
2
OH
O
Cl
2
O 1.5 [30, 38]
1
O
S
Ar N
1
N N
Hal = Cl, Br R = H, Et O
Ar
2
Ar N H
N
O O R
N
S
R
N
O
O
N
R
HalCH2COOR
1
R
OH
CH3CH(Br)COOH
N R
R
1
N
2
SC
2
R
S
Me
1
R
N 1.4 [30]
S R
N
2
RI PT
2
M AN U
R
N
Figure 2. Synthesis of pyrazoline-thiazolidinones via [2+3]-cyclization reactions.
EP
Three-component one-pot reaction that includes [2+3]-cyclocondensation of 4,5dihydropyrazole-1-carbotioamides 1.1 with chloroacetic acid and the further Knoevenagel reaction
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with aromatic aldehydes [33, 34] and isatin derivatives [32] is an effective approach for design of new anticancer agents among the pyrazoline-thiazolidinones 1.10, 1.11 (Figure 3).
ClCH2COOH + ArCHO
O N R
2
N N
O R R R
R
N N
O +
R ClCH2COOH
3
O N
4
R
2
N N
NH2 1.1
1.10
R
N
Ar 1
2
1
S
S
3
S N
R
1
O 1.11
Figure 3. Three-component one-pot reactions in synthesis of 2-pyrazolinyl-4-thiazolidinones.
R
4
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The reaction between pyrazolyl-imines [39, 40] or pyrazolyl-hydrazones [41] and thioglycolic acid or its esters is widely used approach for the synthesis of 4-thiazolidinone conjugates 1.12, 1.13 with pyrazole moiety in position 2. A. Khodairy proposed a synthesis of 2substituted 4-thiazolidinone with benzopyrano[2,3-c]pyrazol-3-one fragment 1.14, using N-
2
2
R
3
N
N R3
S
R
N R
N
1
OH
R
N N
Het
Het
N N H
2
O
2
O
S
1
HS R
H N N
N
N R
SC
O
RI PT
cyanoacetyl-benzopyranopyrazolone [42] as a starting compound (Figure 4).
O
R
N N
O
1
R
1.13
N
1.12
N
M AN U
O
N
O
1
R
O
N
N
1.14
S
O
N
O
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Figure 4. Thioglycolic acid reagent in thiazolidinone ring-formation reactions.
Another direction for synthesis of pyrazole-substituted thiazoline 1.16 (Figure 5) was realized by the creation of pyrazole moiety via the reaction between 5-fluoro-2-hydrazino-4-
F
NH2C(S)NHNH2
AC C
F
EP
hydroxy-4,5-bis(trifluoromethyl)-1,3-thiazoline 1.15 with acetoacetone [43, 44].
CF3
O
O CF3
OH N
CF3
S
H N
CF3
F
Me
Me CF3
OH N
CF3
S
Me N
NH2 1.15
O
F
N 1.16
Me
Figure 5. Example of pyrazole formation in the synthesis of pyrazole-thiazolines.
A broad group of pyrazole-thiazolidinone derivatives exemplified by 2-imino-4thiazolidinones (pseudothiohydantoines) 1.18, 1.19 were synthesized via [2+3]-cyclocondensation of pyrazole substituted asymmetric bis-thioureas 1.17 as S,N-binucleophiles with some equivalents of dielectrophilic synthon [C2]2+ (ethyl 2-chloroacetate [45, 46], dimethyl acetylenedicarboxylate
ACCEPTED MANUSCRIPT
[47]). Simultaneously, bioisosteric pyrazolyl-2-iminothiazolidines 1.20 [46] were obtained by reaction of thioureas 1.17 with α-bromoacetophenones (Figure 6). Het
O
R
N N
ClCH2COOEt
S
1.18
H N
H N
Het
O
S
O
MeO
OMe N
N Ar
1.19
Br
Ar R N
Het
N
Het = Ar
S
N H
N H
1.20
N
SC
N
OMe
O R
N Ar
S
Het
RI PT
N N H
N
1.17 O
Het =
O
R R
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Figure 6. Synthesis of pyrazole-thiazolidinones with imine linker group.
Aiming to search for new anticancer or antimicrobial compounds among pyrazolethiazolidinone conjugates the pyrazole-sulfonyl-thioureas 1.21 were used as starting materials. The reaction between compounds 1.21 and ethyl 2-chloroacetate or α-bromoacetophenone resulted in
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formation of the corresponding pyrazole-thiazolidinones 1.22 and pyrazole-thiazolidines 1.23 with sulfonylimine linker group [48-53] (Figure 7). O
Het
S N
AC C
SO2
EP
ClCH2COOEt
R N
1.22
1.21
Br
R Ar
R N
S
S N SO2
Het =
Me
O(S)
N
N
N
N
1
R
Het
Ar
O H N
H N SO2
Ar CF3
N
N
2
R
Het
N N
N Me
N
1
R
N N Ph
1.23
Figure 7. Synthesis of diazole-thiazolidinones/thiazolidines with sulfonylimine linker group.
Another approach for the synthesis of pyrazole derivatives of pseudothiohydantoin 1.26 was suggested by B. Insuasty et al. [54]. The synthesis of target compounds was carried out via
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aminolysis of 5-arylidene-2-thioxo-4-thiazolidinones (5-arylidenerhodanines) 1.24 by 4,5diaminopyrazoles 1.25 (Figure 8). O
H2N
H N S
Ar
N
O
+ S
Me
H N
Me
N S
N
H 2N
N
H2N
Ph 1.25
Ar
Ph 1.26
RI PT
1.24
N
Figure 8. Aminolysis reaction in synthesis of pyrazole-thiazolidinones.
SC
A row of 2-pyrazolyl-hydrazone-thiazolidinones 1.28-1.30 was synthesized via [2+3]cyclocondensation of thiosemicarbazones 1.27 with α-halogenocarboxylic acids derivatives or
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maleic anhydride [55-60]. The pyrazole with bioisosteric 2-thiohydantoin 1.31 [61] and thiazolidine 1.32 [55-60] fragments were obtained by reaction of thiosemicarbazones 1.27 with chloroacetic acid in pyridine or α-bromoacetophenone. However, the reaction of thiosemicarbazones 1.27 with acetic anhydride or iron chloride was accompanied by the formation of pyrazole-thiadiazole derivatives
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1.33, 1.34 [56] (Figure 9).
R
H(Me)
R
O
1
S 1.29 [55]
AC C
O
O
O
EP
OH O
Pyraz O
R
OEt
N
N
Cl
Pyraz
N
Ph N
N Pyraz 1.31 [61]
O
ClCH2COOH(Et)
O
N
ClCH2COOH
BrCH(COOEt)2 Pyraz
N
H N
H N
R
1
Ar
Ac2O Me O
S
Pyraz SO2 N H
Pyraz N Ph
S O 1.33 [56, 60]
Pyraz NH
S
1
R
1
1.34 [56]
O
N
Me N
R
H(Me)
N N
Pyraz
N N
N
N 1.32 [55-60]
FeCl3
Pyraz
1
S
1.27
N
R
N
1.28 [59]
N
1
Br
1
Me
Ar
O H(Me)
S
Me
S O
N Pyraz 1.30 [55-60] S
N
1
R
N
N
N N
1
1
Pyraz Me
Ar
Ph N N
N N
Me
Ph(Het)
Figure 9. Synthesis of pyrazole derivatives with thiazolidinone, imidazolidine and thiazoline fragments in molecules.
ACCEPTED MANUSCRIPT Pyrazole-substituted thiosemicarbazides 1.35 were used for synthesis of the pyrazolethiazolidinones 1.36 with carbohydrazide linker group [62, 63]. The three-component one-pot reaction between thiosemicarbazides 1.35, chloroacetic acid and aromatic aldehydes accompanied
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by formation of the corresponding 5-arylidene-4-thiazolidinones 1.37 [63, 64]. The modification of 1.35 in sulfuric acid medium gave pyrazole-thiadiazole 1.38 [64]. The reaction of compounds 1.35 with α-bromoacetophenones was accompanied by the formation of corresponding pyrazolethiazolidine conjugates 1.39 [62-64] (Figure 10).
N
N N H
O 1
R
Ar
N N
ClCH2COOEt
ClCH2COOH, ArCHO
S
O
Pyraz
NH
N H
O
H N
H N
N
H2SO4
1
S
N
R
S
Ar N
O
Pyraz 2
Ph 3
N
N
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R N N
H Ph N
1.36
1.35
1.37
Pyraz
S
O
M AN U
Pyraz
SC
1
R
O
R
Ar
Br
1
1
N
N N H
1.38
R
O Pyraz
Ph
N
S
Ar
1
1.39
EP
Figure 10. Pyrazole-substituted thiosemicarbazides in synthesis of pyrazole-thiazole hybrids.
AC C
3. The main methods for synthesis of 4-thiazolidinones with pyrazole/pyrazoline moiety in position 3
Synthesis of 2-diazole-substituted 4-thiazolidinones was achieved via the [2+3]cyclocondensation of the pyrazole-based asymmetric thioureas 1.17 as S,N-binucleophiles (see Figure 6). At the same time, the numerous papers represent the data about obtaining of 4thiazolidinones with diazole moiety in 3 position (compound 2.1, Figure 11), in particular via the reaction of thioureas with ethylchloroacetate [65].
ACCEPTED MANUSCRIPT Het
H N
H N
ClCH2COOEt
Ph
Het
N N
R S
S
N
O
N H
2.1
1.17
Me
Het =
N
Me
RI PT
Figure 11. Synthesis of 3-diazole-substituted 4-thiazolidinones.
The dithiocarbamate method of 2-thioxo-4-thiazolidinones (rhodanines) synthesis is a convenient and often used variant of the synthesis of 4-thiazolidinone derivatives based on the
SC
[2+3]-cyclocondensation [5]. R.M. Mohareb et al. had successfully applied the dithiocarbamate method for the synthesis of 3-(pyrazol-5-yl)-2-thioxo-4-thiazolidinone via two-stage process based
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on the reaction between 3-phenyl-5-aminopyrazole 2.2 and carbon disulfide in an alkaline medium and subsequent cyclization with ethyl 2-bromoacetate [66]. The presence of the methylene group in the position 5 of thiazolidine cycle allowed the authors to carry out the structural modification of pyrazole-thiazolidinone 2.3 in the Knoevenagel reaction (ethanol medium, catalyst - piperidine) and
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diazotization to get the 5-substituted derivatives 2.4, 2.5. Starting from rhodanine 2.3 the alternative methods for the synthesis of condensed pyrano[2,3-d]thiazole system 2.6 with pyrazole moiety in position 3 were proposed, namely the reaction of 5-arylidenerhodanines 2.5 with malononitrile or
EP
by heterocyclization of compound 2.3 with benzylidenemalononitrile. Pyrazole-thiazolidinone 2.3 in the presence of hydrazine hydrate undergoes ring transfomation with obtaining of the pyrazole-
AC C
triazole 2.7 (Figure 12).
ACCEPTED MANUSCRIPT Ph
Ph CS2
N
NH2
N H
N
DMF, KOH
NH
N H
SK
S
2.2 Ph N
OEt
Br
S
S
+ N NCl
Ph
N
N S
2.4
N H
N
N
N
2.7
CN
PhCHO
Ph
CN
NC
Ph
Ph
CH2(CN)2 N H
S
N 2.5
Ph
Ph
O
N
M AN U
N S
SC
NH2 O
2.6
NH
HS
2.3
S
Ph
NH2NH2
Ph
O
S N
NH
O
RI PT
N
O
N
Ph
NH
S
N H
N
S
Figure 12. Syntesis and modification of 3-pyrazole-substituted rhodanines.
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Various 4-thiazolidinones were synthesized by reaction of α-mercaptocarboxylic acids (especially thioglycolic acid) with isothiocyanates (R–N=C=S). Thus, a pyrazole-thiazolidinone 2.8 with phenyl sulfonamide linker group was obtained based on the mentioned approach [67]. There
EP
were described the synthesis of 3-pyrazole-substituted or polyheterocyclic derivatives of 4thiazolidinones 2.9, 2.10 based on the reaction between thioglycolic acid and corresponding imines
AC C
and methylidene-hydrazydes or three-component reaction involving thioglycolic acid, aromatic aldehydes and heterocyclic amines containing diazole fragment [68-72]. The reaction of isatin with heterocyclic amines led to Schiff’s bases which were further reacted with thioglycolic acid to form 3-diazole-substituted indoline-spiro-thiazolidinones 2.11 [73, 74] (Figure 13).
ACCEPTED MANUSCRIPT R O
N
N
Ar
O
R
Me
N
N
N R
R
N
Ph
N
2
R
1
NH
HS
N H
R
N
O
2.11 N N
N
N H
S
N N
N H
NCS
S
NH
N
Ar
S
2.9
S
M AN U
N Ph
N
N H
O
N
O
O
O
3
R
SC
Ar
N
Ar
HN
Ph N
N
O
O
O Ac
2
R
N
O
1
1
R
3
OH
N Ph Me
N
O
R
N
N
N Ar
O
R=
N H
RI PT
S
N
2.10
or ArCHO + RNH2
O
N
N H
Ar S
Ar
H N
R=
2.8
S
Figure 13. α-Mercaptocarboxylic acids reagent in the synthesis of 3-subtituted thiazolidinones.
The reaction between trithiocarbonyl diglycolic acid and amines in alcohol or alcohol-water
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medium (Holmberg synthesis) is a convenient and effective method for synthesis of 3-substituted rhodanines, especially based on the aromatic amines and carboxylic acid hydrazides [5]. The
EP
mentioned reaction was used by Augustin M. et al. for synthesis of rhodanine 2.12 with benzopyrazole fragment in position 3 [75] (Figure 14).
AC C
NH2 N
N H
OH S
+
H N
O N O
S
N S OH O
S
S 2.12
Figure 14. Holmberg synthesis for benzopyrazole-rhodanine.
The method for synthesis of pyrazole-thiazolidinone 2.15 (Figure 15) with acetamide linker group was proposed based on the reaction of 5-arylidenerhodanine-3-acetic acid 2.13 and 5-
ACCEPTED MANUSCRIPT
aminopyrazole 2.14 in DMF in the presence of HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate) [76]. 2
OH N
O
O
N N
N
N
O R1
1
R
Ar
S
S
2.14
Ar
2.15
RI PT
2.13
R
H N
N
+ HN 2
S
S
2
R
O
Figure 15. Synthesis of pyrazole-thiazolidinone conjugates via acylation reaction.
SC
Synthesis of structurally related azolidine-pyrazolines 2.16, 2.17 was proposed based on Nalkylation reaction of potassium salts of 2,4-thiazolidinedione, hydantoin and their 5-arylidene
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derivatives, obtained in situ (Figure 16). 2-Chloro-1-(3,5-diarylpyrazolin-1-yl)-ethanones were successfully used as alkylating agents [77]. 1
Ar
Ar
2
O
O
H N
N N X
O
2
1
Ar
O
Ar
O 2.16
KOH EtOH X = S, NH
Cl
O
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X
O
X
2
1
Ar
Ar O
N N
3
N N
N
H N
Ar
O N
KOH EtOH
X 3
Ar
O O
2.17 X = S, NH
EP
Figure 16. Synthesis of pyrazoline-azolidinone conjugates via alkylation reaction.
4. The main approaches to the synthesis of 4-thiazolidinones with pyrazole/pyrazoline moiety
AC C
in position 5
One of the main approaches for the synthesis of 5-pyrazole/pyrazoline substituted 4thiazolidinones is based on Knoevenagel reaction of 4-thiazolidinones [5]. A numerous 1-, 3- and 5substituted pyrazole-4-carbaldehydes were used as carbonyl compounds and allowed to obtain a series of new 2,4-thiazolidinediones [78-81], rhodanines [82-86] and 2-imino-4-thiazolidinones with pyrazole moiety (compounds 3.1) [87-89]. The synthesis of pyrazolone-thiazolidinones 3.2 was
conducted
by
reaction
of
3-arylrhodanines
with
4-acetyl-5-methyl-2-phenyl-2,4-
ACCEPTED MANUSCRIPT
dihydropyrazol-3-one [90]. Position 5 of thiazolidine cycle was successfully modified in diazo coupling reaction [91] using pyrazolyl diazonium chloride yielding compound 3.3 (Figure 17). Me
H
Ar
N
N Me
O
R
5
R
N
2
R
N
O
R
N N 3 R
N N N H
5
ClPh
O
Me
H N
N N N N H
3.1
R1 = O, S, NH, N-Ar, N-N=R
SC
N
1
R
S
4
R
+
Ph
2
N
Me
3.2
R
H
R
S
Ph
O
3
1
Me N N
O
N
O
N Ph
S
S
R
RI PT
O
4
O
Me
S
S
3.3
M AN U
Figure 17. Knoevenagel and diazo coupling reactions for synthesis of pyrazole-thiazolidinones.
The synthesis of pyrazoline-indoline-thiazolidinone conjugates 3.5, 3.6 was realized by the Knoevenagel reaction of pyrazoline-isatines 3.4 with 2,4-thiazolidinedione, 2-thioxo-4-
TE D
thiazolidinone and 2-amino4-thiazolidinone in the acetic acid medium and in the presence of sodium acetate [92] (Figure 18).
R
O
3
R
O
EP
Ar
3
2
O
N Ar
1
O
K2CO3, DMF
AC C
S
X
AcONa, AcOH
R
N
N H
O
H N
O
O
N
H N
N
N
Ar
1
O
2
S
3
O N
Cl
Ar
3.4
O
O
1
3
NH2
S 2
Ar
N
N
R
AcONa, AcOH
N
N O
O N
N 1
Ar
X
Ar N
S
O 3.6
Figure 18. Synthesis of pyrazoline-indoline-thiazolidinone conjugates.
NH2
2
3.5
Ar
ACCEPTED MANUSCRIPT
The synthesis of pyrazolone-thiazolidinones 3.7 (Figure 19) was achieved based on the reaction between isonitrosorhodanines and 5-methyl-2,4-dihydropyrazol-3-one using piperidine as basic catalyst [93]. CH3 R
N S
N
HN
S N
piperidine
S
R
N
N N H
N
HO
O
O
O
RI PT
O
CH3
3.7
SC
Figure 19. Synthesis of pyrazolone-thiazolidinone conjugates.
S
Magdy Ahmed Ibrahim et al. investigated a modification of 5-[4-oxo-4H-chromen-3-
M AN U
yl)methylene]-1,3-thiazolidin-2,4-dione 3.8, in particular in the ring-transformation reactions of chromene cycle with hydrazine hydrate and phenylhydrazine. These reactions allowed to obtain the corresponding pyrazole-thiazolidinones 3.9 [94]. Using hydrazine hydrate the structure of final compounds depended on the reaction medium. Thus, 1N-non-substituted pyrazoles were obtained in
TE D
alcohol medium and in the presence of sodium ethylate, while 1N-acetylderivatives were formed in acetic acid. The reaction of the compound 3.8 and 1-phenylpyrazolidin-3,5-dione in the presence of sodium ethylate led to formation of polyheterocyclic system 3.10 (Figure 20).
O
O
EP
H N
NH2NH2 or PhNHNH2
AC C
S
N
O
O
H N
N O
R
R = H, Ph 3.9
O
H N
H N
S
O
S
Ph
O OH
N Ph
O O
N
OH
O O
3.8
N
3.10
Figure 20. Chromene ring-transformation reactions in synthesis of thiazolidinone-diazole hybrids.
Synthesis of 5-pyrazolyl-4-thiazolidinones with ethylene linker group 3.11 was performed via the [2+3]-cyclocondensation reaction of thiourea with γ-pyrazolyl-α-chlorobutanoates [95].
ACCEPTED SMANUSCRIPT
R Me
Cl
H 2N
OEt
N N
NH2
Me
H N
N
O
Me
O
R
O
S
N Me
3.11
RI PT
Figure 21. Synthesis of 5-pyrazole-substituted thiazolidinones via [2+3]-cyclocondensation.
Pharmacologically attractive 5-(5-oxo-4,5-dihydro-1H-pyrazol-4-yl)rhodanines 3.12 (Figure 22) were synthesized following heterocyclization of 2-thiazolidinyl-3-oxobutanoates with phenylhydrazine or conjugation of 4-bromopyrazolon-5-ones to 3-arylrhodanines [96].
O N
PhNHNH2
O
N
N
S
S EtO
Me
Ar
Ar
N
Ph N
S
Ph
Ar N
O
N
O
Br O
S
M AN U
Me
SC
Me
O
3.12
O
S
S
Figure 22. Alternative approaches for the synthesis of thiazolidinone-pyrazolones.
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The group of pyrazoline-thiazolidinones 3.13 was obtained by reaction of 5-bromo-2,4thiazolidindione with 3,5-diarylpyrazolines in alcohol medium (Figure 23). The synthesized compounds were modified in position 3 of thiazolidine cycle by Mannich reaction with secondary
EP
cyclic amines and alkylation reactions forming 3.14, 3.15 [97]. O
2
Ar
AC C
N
H N
NH
Ar
1
Br
S
Ar
2
Ar O
N
O
N
EtOH
S
1
EtOH Ar
2
O X
N S 1
Ar
3
Ar
2
Ar
N
N
O
3.14
Figure 23. Synthesis and modification of pyrazoline-thiazolidinones.
H N Ar3
O
N
N
N
S
1
H N
Cl
O Ar
N K O
EtOH
X
N
O
3.13 HN
O
N
KOH NH
Ar
2
N
S 1
Ar
O O
3.15
ACCEPTED MANUSCRIPT The following approach to the synthesis of pyrazoline-thiazolidinone conjugates 3.16 with carbonyl methylidene linker group was based on the acylation reaction of 3,5-diarylpyrazolines (Figure 24). The further reaction of substances 3.16 with chloroacetamides via N-alkylation reaction
RI PT
led to derivatives 3.17 [97]. 3
O
H N O
S
2
Ar
O
O
1
Cl
O
Et3N, dioxane
Ar
H 3 N Ar
S
N
N
O
Ar
O
N
O
S
1
Ar
SC
NH
O
O
Cl
N
H N
HN
KOH, EtOH
O
N N
2
Ar
2
3.16
M AN U
Ar
1
Ar
3.17
Figure 24. Synthesis and alkylation of thiazolidinone-pyrazolines 3.16.
To explore the structure-antitrypanosomal activity relationship the pyrazoline-thiazolidinone
TE D
conjugates 3.18 were synthesized through the reaction of the 5-ethoxymethylidenerhodanines with 3,5-diarylpyrazolines (Figure 25). 5-Pyrazoline substituted 4-thioxo-2-thiazolidinones 3.19 were obtained under the same conditions [98].
1
R
EP
X
N
S
R N
2
Ar
Y
AC C
O
X
Ar
N H
N S
EtOH
Me
Y
N N 1
Ar
Ar
2
3.18. X = O, Y = S, R = Alk, Ar 3.19. X = S, Y = O, R = H
Figure 25. Synthesis of 5-pyrazoline substituted thiazolidinones.
To continue the above mentioned study, 5-pyrazoline derivatives of 4-thiazolidinone 3.21 with oxoethylamino-methylene linker group were synthesized by modification of rhodanine-5carboxylic acid 3.20 in the reaction with pyrazolines and in the presence of DCC (dicyclohexylcarbodiimide) [98] (Figure 26).
ACCEPTED MANUSCRIPT 1 Ar O N S O
O
Me
Me N
NH2CH2COOH S
AcOH
Me
HO
S
S
NH
N H
N
N S
S
NH
EtOH 3.20
Me
O
2
Ar
N
1
Ar
N
O
O
3.21
2
Ar
RI PT
Figure 26. Synthesis of pyrazoline-rhodanine conjugates with oxoethylamino-methylene linker group.
SC
5. Biological activity of pyrazole-thiazoldinones derivatives and reated heterocyclic hybrids 5.1. Antitumor activity of pyrazole/pyrazoline-thiazolidinone hybrids
M AN U
Antitumor activity evaluation is promising for the thiazolidinones with pyrazoline fragment. The in vitro anticancer activity of thiazolidinones with pyrazoline cycle in position 2 (4.2) or 4 (4.3) of thiazolidine was tested by the National Cancer Institute (NCI) and most of them displayed anticancer activity on leukemia, melanoma, lung, colon, CNS, ovarian, renal, prostate and breast
TE D
cancers cell lines. The most efficient anticancer compound 4.1 was found to be active with selective influence on colon cancer cell lines, especially on HT 29 (lgGI50 = -6.37) [33]. The SAR study revealed that: (1) anticancer activity of compounds is sensitive to the nature of substituent in
EP
position 5 of thiazolone cycle, (2) introduction of p-OH group in 5-benzylidene fragment enhanced potency, and (3) the positional isomers, namely 2-pyrazoline (4.2) and 4-pyrazoline (4.3)
AC C
substituted thiazolones are promising compounds for further optimization (Figure 27).
ACCEPTED MANUSCRIPT O N MeO
S OH
N HO
4.1
N OMe
pGI50 = 5.61
Ph
Ar
1
N
N
2
O
2
O
N
N
Ar
RI PT
Ar
Pyrazoline cores in positions 2 and 4 are attractive
N
N
S
S
1
3
Ar
C5-fragment (Ar3CH=) is essential
Ar
4.2
SC
4.3
Ar
3
M AN U
Figure 27. Antitumor activity for pyrazoline-thiazolidinone based hybrids.
Novel pyrazoline-thiazolidinone-isatin 4.4 and pyrazole-indoline-2-one 4.5 conjugates were designed as potential anticancer agents (Figure 28). The most effective anticancer compound 4.6 was found to be active with a mean GI50 and TGI values of 0.071 µM and 0.76 µM, respectively
TE D
and demonstrated the highest antiproliferative influence on the non-small cell lung cancer cell line HOP-92 (GI50 < 0.01 µM), colon cancer line HCT-116 (GI50 = 0.018 µM), CNS cancer cell line SNB-75 (GI50 = 0.0159 µM), ovarian cancer cell line NCI/ADR-RES (GI50 = 0.0169 µM) and renal
EP
cancer cell line RXF 393 (GI50 = 0.0197 µM). The SAR study revealed that: (1) potent anticancer activity of tested compounds depended on the presence of a combination of three heterocycles in
AC C
one molecule, thus the pyrazoline-thiazolidinone-isatin conjugates were more active in comparison with pyrazoline-thiazolidinone or pyrazole-indoline-2-one systems; (2) attachment of halogen (Br or Cl) to 5-position of isatin scaffold allowed to gain one log unit of activity (GI50 level), in comparison with 5-unsubstituted isatin analogs; (3) introduction of a methyl group or CH2COOH group at 1N-position of isatin fragment led to the loss of activity; (4) the nature of a substituent in the 5-aryl fragment also had an influence on the antitumor activity. Therefore, the introduction of electron-withdrawing group – 4-chlorine improved the antiproliferative activity in comparison with electron-donor 2-OH, 4-OMe and 4-NMe2 groups. This would indicate that decreased of electron
ACCEPTED MANUSCRIPT
density on 5-aryl moiety is important for the inhibitory activity; and (5) substitution of the phenyl fragment in 3 position of pyrazoline cycle on naphthalene-2-yl substituent did not have significant influence on antitumor activity, but introduction of the 4-methoxyphenyl group in the mentioned position limited this effect [32]. Positions for optimization
2
R
RI PT
2
R
N Ar
3
O
Significant increase of activity 1
S Ar
N N
R
N S
O
2
Ar
1
N
Significant increase of activity
R
N N Ar
4.2
1
2
Ar
4.4 O N
N H
O
1
N
N
N
O
Ar
2
4.5
M AN U
S
N
1
Ar
SC
O
N
4.6 GI50 = 0.071 µM TGI = 0.76 µM
MeO
TE D
Figure 28. Isatin-based conjugates with antitumor activity.
Y. Rajendra Prasad et al. synthesized a series of pyrazoline-thiazoles 4.7, 4.8, and examined
EP
their antitumor activity in vitro on tumor lines: Hela (human cervix carcinoma cell line), A549 (human lung adenocarcinoma cell line), MCF-7 (human breast adenocarcinoma cell line), A2780
AC C
(human ovarian cancer cell line) and BGC-823 (human gastric cancer cell line), using the MTT method. As a result of studies two hit-compounds 4.10 and 4.11 were selected. SAR analysis showed that the determining factor for exprssion of antitumor activity is the structure of the substituent in the 4 position of thiazole (Figure 29). A modification of the ester group into hydrazide and, subsequently, a hydrazone gave the potentiation of antitumor properties. At the same time, pyrazoline-thiazolidinones 4.9 had no significant cytotoxicity [35].
ACCEPTED MANUSCRIPT Ph N
N
F
H N
N
N
N
N S F
F
O
S
Positions for optimization R
N N
O
S F
Ph
N
N
Ar
N
F
R = OEt, NH-NH2, NH-N=CHAr
N
O
S F
F
F
4.8
increase of activity
N
N
S F
4.7
Ph
SC
N
4.11
IC50 (Hela) = 4.86 µM IC50 (A549) = 1.21 µM IC50 (BGC-823) = 1.20 µM
IC50 (Hela) = 4.23 µM IC50 (A549) = 0.96 µM IC50 (MCF-7) = 1.20 µM
Ph
Me
F
F
4.10
N
F
RI PT
Ph
4.9
M AN U
Figure 29. Thiazole-pyrazoline hybrids with antitumor activity.
The series of pyrazoline-thiazolidine-based compounds were tested for antitumor activity according to standard NCI protocol and 4-thiazolidinone derivatives with pyrazoline fragment 4.12,
TE D
4.14, 4.17 showed moderate cytostatic effect. The group of publications includes the synthesis of these pyrazoline-thiazolidinones 4.12, 4.14, 4.17 and pyrazoline-thiazolidines 4.13, 4.15, 4.16, 4.18 with diversity of substitution in pyrazole core. The analysis of mentioned results demonstrates that
EP
the modification of pyrazoline fragment is not crucial to the implementation of antineoplastic action
AC C
(Figure 30). This statement is evidenced by the level of efficiency of compounds 4.12-4.18 with moderate rates of effective concentration [48-51].
ACCEPTED MANUSCRIPT
Pyrazoline-thiazolidinones
Pyrazoline-thiazolidines Ph
Ph N SO2
N N
N
N SO2
N
S
Ph
N
N
O
N SO2
N
S S
4.14 GI50 = 46.8 µM
N
O N SO2
N Me
S
4.17 GI50 = 44.7 µM
O
N SO2
N
M AN U
N N
Ph
Me Ph
S
4.15 R = phenyl GI50 = 54.9 µM 4.16 R = benzoyl GI50 = 42.6 µM
SC
S
Ph
N
RI PT
N SO2
N
R
Cl
O N
S
4.13 GI50 = 41.7 µM
4.12 GI50 = 30.2 µM
Cl
Ph
N
O
N
N
Ph
S
4.18 GI50 = 20.04 µM
Me
TE D
Figure 30. Antitumor thiazolidinone/thiazole derivatives with pyrazoline moiety in 2 position.
Magdy I. El-Zahar et al [55] synthesized a group of benzofuran-pyrazoles with various heterocycles, including thiazole (4.19) and thiazolidine (4.20) fragments for screening of antitumor
EP
activity on lines: HEPG2 (liver carcinoma cell line) and HELA (cervix carcinoma cell line). Interestingly, each of these compounds showed selective effect on one of the lines similar to 5-
AC C
fluorouracil (Figure 31).
H N
O
N
O S N S
N
O
Me N N
N N Ph
Ph 4.19 GI50 = 5.0 µg/ml (HEPG2)
4.20 GI50 = 1.2 µg/ml (HEL A)
Figure 31. Antitumor benzofuran-pyrazoles with thiazolidinone/thiazole fragments.
ACCEPTED MANUSCRIPT
Synthesis and study of antitumor activity of pyrazole-thiazolidinone-triazoles on lung cancer MCF-7 line were conducted by Arun M. Isloor et al. [40]. Among the studied conjugates the compound 4.21 was the most active with the effective concentration IC50 = 22 µg/mL. The presence of o-tolyl fragment was most favorable for the anticancer effect, while substitution with naphthyl
Me
N
SH S
N
N
O
O
H N
SH
N O
N
CH3
N
N
1
R
N
S N N H
4.21 GI50 = 22 µg/ml
Cl
O R2
Increase of activity
SC
N
RI PT
ring caused complete loss of activity (Figure 32).
M AN U
Figure 32. Antitumor activity of pyrazole-thiazolidinone-triazoles on lung cancer.
An important achievement in the study of anticancer pyrazole-thiazolidinone hybrid compounds is the establishing of the necroptosis inhibition for pseudothiohydantoin derivatives
TE D
with pyrazole moiety in 5 position (Figure 33). Among these derivatives a potential inhibitor Necrostatin-7 (Nec-7) was identified with the activity index of 10.6 µM. Further studies aiming to optimize of Nec-7 molecule, were focused on the modification of thiazole fragment, replacement of
EP
substituents in the phenyl ring and replacement of pyrazole cycle by other heterocycles. It was established that the replacement of thiazole fragment by the 1,3,4-thiadiazole led to the complete
AC C
loss of activity. The introduction of the methyl group in the 4 position of thiazole caused a slight gain of inhibitory action, while presence of methyl in the 5 position of thiazole had a negative effect. The most effective direction for modification of Nec-7 was the replacement of fluorine atom in the 4 position of benzene core. Thus, the introduction of morpholine (4.22), phenol (4.23) and phenyl sulphanilic (4.24) fragments allowed to get 3-7 fold potentiation in comparison to Nec-7. In general, it should be noted that the presence of the substituent in the 4 position and its nature was crucial for the implementation of necroptosis inhibitory activity, because the change of a fluorine atom position was accompanied by loss of activity. The authors synthesized a group of related
ACCEPTED MANUSCRIPT
compounds with aromatic heterocycles (triazole and isooxazole) to establish the impact of pyrazole cycle for activity. This modification resulted in the loss of inhibitory activity, which confirmed the importance of pyrazole moiety in the analogs Nec-7 [87]. O N O
NH
O Essential heterocyclic cores
S
S
N NH
NH
N
N
N
4.22 EC50 = 2.93 µM
S
O
N
H N N
para-position is optimal
N
Ph
Ph SO2
N NH
S
4.23 EC50 = 1.29 µM
O
M AN U
F Nec-7 EC50 = 10.6 µM
N
N
N NH
S
NH
SC
N
RI PT
S
S
S
NH
4.24 EC50 = 1.78 µM
Figure 33. 5-Pyrazoline-substituted pseudothiohydantoines as promising necroptosis inhibitors.
TE D
The study of antitumor activity for pyrazole-rhodanines allowed to identify the compound 4.25, which proved effective inhibitory effect on the most of the 60 tumor lines at micromolar concentrations according to NCI protocol (Figure 34). The substance 4.25 was characterized by a
EP
selective effect on leukemia and lung cancer cell lines - especially on HOP-92 (lung cancer) with the values of effective concentration and cytotoxicity GI50 = 0.62 µM and LC50> 100 µM,
AC C
respectively [82].
Ph
O
N
N
Ph
S
4.25
NH S
CCRF-CEM (Leukemia) GI50 = 2.50 µM RPMI-8226 (Leukemia) GI50 = 2.52 µM EKVX (Non-Small Cell Lung Cancer) GI50 = 3.03 µM, NCI-H522 (Non-Small Cell Lung Cancer) GI50 = 2.96 µM HOP-92 (Non-Small Cell Lung Cancer) GI50 = 0.62 µM
Figure 34. Selective antitumor activity of pyrazole-rhodanine 4.25.
Manal Sarkis et al. carried out the synthesis of new bis-thiazolone derivatives as potential inhibitors of CDC25V phosphatase (specified enzyme involved in cell cycle progression and
ACCEPTED MANUSCRIPT
unregulated tumor development). Aiming to investigate the selectivity, the affinity of the compounds was studied to PTP1B (Protein Tyrosine Phosphatase 1B) and VHR (Vaccinia virus H1 Related – a dual-specificity phosphatase). Overall 31 compounds from bis-thiazolidinone group were synthesized and most of them displayed inhibitory activity with micromolar IC50 values lower
RI PT
than the corresponding monomers. Mentioned group of the compounds included the thiazolidinoneindazole conjugate 4.26 (Figure 35). It was established that the replacement of a 4-hydroxyphenyl fragment with indazole was accompanied by selective inhibition of CDC25B phosphatase and loss
O N
H N
O
N
N H
4.26 HO
N S
IC50 ± SEM (µM) or % of phosphatase inhibition at 100 µM CDC25B PTP1B VHR 2.9 ± 0.8 18% 25%
M AN U
S
N
SC
of PTP1B inhibitory activity (abolished PTP1B inhibition) [99].
HN
N
TE D
Figure 35. Bis-thiazolone with indazole fragment as potential inhibitor of CDC25V phosphatase.
Screening of in vitro antitumor activity for 5-pyrazoline substituted 4-thiazolidinones
EP
(compounds 4.27 and 4.28) was carried out within the DTP NCI [77, 97]. Overall tested substances had a moderate activity, but two compounds were identified with selective effect on leukemia cell
AC C
lines with effective concentration GI50 2.12-4.58 µM (4.29) and 1.64-3.20 µM (4.30). SAR analysis showed that the introduction of the linker group between heterocycles promoted the potentiation of antitumor activity, however, modification of 3N-position of thiazolidinone cycle via Mannich reaction and alkylation was not effective approach to optimization of hit-compounds (Figure 36).
2
Ar
ACCEPTED MANUSCRIPT O
O N N
N S
O
1
Modification of N3 position decreased antitumor activity
NH
2
N
S Ar
Ar
NH
O
Linker elongation increased antitumor activity
O 1
Ar
4.27
4.28
O
O
H N
H N N
S
N
N O
N
O
O
O 4.29 GI50 = 2.12 - 4.58 µM
HO
S
RI PT
MeO
4.30 GI50 = 1.64 - 3.20 µM
Cl
M AN U
SC
Figure 36. Antitumor activity of 4-thiazolidinones with pyrazolines in 5 position.
5.2. Antimicrobial and antifungal activity of pyrazoline-thiazolidinones The search for new antimicrobial and antifungal agents among pyrazoline-thiazolidinone related conjugates is a promising direction for biological testing of mentioned compounds. Mervat M. El-Enany et al. synthesized the group of 4-thiazolidinones and thiazoles with pyrazoline
TE D
fragment in 2 position and studied their antimicrobial activity against Gram-positive (Staphylococcus aureus, Bacillus subtilis), gram-negative bacteria (Escherichia coli, Pseudomonas
EP
aeruginosa) and fungi Candida albicans [24]. However, the compound 4.31 was inactive to any of the microorganisms, while activity of 4.32 on Bacillus subtilis appeared commensurate with
AC C
Amoxacillin and Propenicillin (Figure 37). The research of Bakr F. Abdel-Wahab et al. was more successful. The authors synthesized a group of triazole-pyrazoline-thiazoles and corresponding 4thiazolidinones and studied their activity against gram-positive bacteria (Staphylococcus aureus ATCC 29213, Bacillus subtilis ATCC6633, Bacillus megaterium ATCC 9885, Sarcina lutea), gram-negative
bacteria
(Klebseilla
pneumonia
ATCC13883,
Pseudomonas
aeroginosa
ATCC27953, Escherichia coli ATCC 25922) and fungi (Saccharomyces cerevisiae and Candida albicans NRRL Y-477) compared with Ciprofloxacin and Ketoconazole [23]. Among the tested thiazole-pyrazolines compound 4.33 showed the highest activity for strain Pseudomonas
ACCEPTED MANUSCRIPT
aeroginosa (MIC = 8.25 µg/mL), which was twice higher than for Ciprofloxacin. Activity of 4.34 appeared commensurate with the drug for bacteria Staphylococcus aureus and Bacillus subtilis (MIC = 8.25 µg/mL). At the same time 4.35 showed a high antifungal activity (MIC = 8.25 µg/mL). It should be noted that the replacement of thiazole fragment with the 4-thiazolidinone was
RI PT
accompanied by the loss of antimicrobial activity against most types of bacteria and fungi, but compound 4.36 showed the highest activity in Bacillus megaterium and Escherichia coli, which were much less sensitive to the action of thiazole-pyrazolines (Figure 37). Study of antimicrobial
SC
activity for structurally related quinoline-pyrazoline-thiazolidones 4.37 against strains Escherichia coli (MTCC 443), Pseudomonas aeruginosa (MTCC 1688), Staphylococcus aureus (MTCC 96),
M AN U
Streptococcus pyogenes (MTCC 442) and antifungal effect on Candida albicans (MTCC 227), Aspergillus niger (MTCC 282) and Aspergillus clavatus (MTCC 1323) evidenced of their minor or moderate activity on most types of microorganisms with MIC values range = 50-500 µg/mL [25]. However, among the above groups of compounds 4.38 could be selected, which showed 2-8 times higher bactericidal activity in experiment than Ampicillin and was twice active than Griseofulvin on
TE D
fungi. The mentioned compound showed the highest activity with the value of MIC 12.5 µg/mL to Pseudomonas aeruginosa (Figure 37). Cl
EP
Cl
Br
AC C
N
F
R
S Cl
N
N
N
N S
Br
4.31
O
4.32
S
F
N N
N N
N
N N
N
Br N N
4.33 R = H, 4.34 R = Cl, 4.35 R = Br
Me
O
Me
N
N N
N
Me
S
4.36
Me
Cl
N
Ar Me
N N O
S
+
N N
Me
N
O
N
4.37 O
S
Figure 37. Pyrazoline-thiazolidinone hybrids with antimicrobial activity.
4.38
N
O
ACCEPTED MANUSCRIPT C.S. Reddy et al. performed the synthesis and study of antimicrobial activity of thiazolidinone-pyrazoles 4.39 against the Bacillus subtilis, Staphylococcus aureus, Escherichia coli and Staphylococcus pyogenes. It was established the moderate effect of mentioned compounds
RI PT
(MIC = 6.25-50 µg/mL) (Figure 38). The introduction of chlorine, nitro or hydroxyl groups in the para-position of the benzene ring resulted in 2-4 fold potentiation of activity in comparison to 3phenyl-4-thiazolidinones. However, replacement of the phenyl moiety to pyridine (4.40) or
R
increase of activity
Me N
Ph
Me
N
S
N 4.39
Me
O
N
N S
N
M AN U
O
Me < Cl-, NO2 or OH
SC
pyrimidine was particularly effective, which allowed to get 4-8 fold enhance of efficiency [100].
Ph
N Me
4.40
TE D
Figure 38. SAR analysis of antimicrobial pyrazole-thiazolidinone hybrids.
The pyrazole-thiazolidinones 4.41 or pyrazole-thiazoles 4.42, coupled by hydrazone linker group were investigated as promising agents with antimicrobial and antifungal activity. It was found
EP
that the compound 4.41b (R = Me) showed comparable activity (MIC = 25 µg/mL) with Ampicillin
AC C
against E. coli, and the compound 4.41c (R = Cl) appeared to be the most active on C. albicans (MIC = 12.5 µg/mL) (Figure 39). Overall, pyrazole-thiazolidinones 4.41 had higher activity than related pyrazole-thiazoles 4.42 [60]. Adnan A. Bekhit et al. synthesized the pyrazoline-thiazoles and thiazolidinones with sulfanilamide group. Among the studied pyrazole-thiazolidinones 4.43 and pyrazole-thiazoles 4.44 the compounds 4.43b (R = Me) and 4.44a (R = H) (Figure 39) were most effective against E. coli (MIC = 25 µg/mL) [56].
ACCEPTED MANUSCRIPT R
R
Br
Br N
Ph
N
N 4.41
N
S
N
S
S
N
N
N
N
Ph Ph
4.42
Ph
R = H (a), Me (b), Cl (c)
Ph
N
N
O
N
S O
N
N N Me
N
S
N
S 4.43
S O
Me Br
SC
N
O
N
O
N N
N
R
N
R
RI PT
O
S
N
Me
Me
4.44
M AN U
Figure 39. Antimicrobial and antifungal pyrazole-thiazolidinones/thiazoles, coupled by hydrazone linker group.
The study of wide range of antimicrobial and antifungal activities of new benzofuranyl-
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pyrazoles with thiazolidinone fragment was conducted by Bakr F. Abdel-Wahab et al. The compound 4.45 showed activity against C. albicans and Bacillus subitilis, and thiazole-derivative 4.46 was effective against the E. coli [62] (Figure 40). To continue the research of pyrazole
EP
derivatives with different heterocycles, authors conducted the synthesis of new derivatives of pyrazole with thiophene fragment 4.47-4.49, including pyrazole-thiazolidine 4.50 (Figure 40) and
AC C
offered a wide range of biological studies, including the evaluation of antimicrobial activity against the following microorganisms: Staphylococcus aureus ATCC 29213, B. subtilis ATCC6633, Salmonella typhi, Enterobacter Cloaca ATCC3047, Klebseilla peneumoniae ATCC13883, Pseudomonas. aeroginosa ATCC27953, E. coli ATCC 25922, Enterococcus faecalis ATCC29212, Mycobacterium phlei, Saccharomyces Cervesia and Candida Albicans NRRL Y-477. Among the tested compounds 4.47 and 4.49 showed hihg/good or moderate efficiency against all strains of microorganisms. While compound 4.48 had proved to be the most effective on Enterococcus faecalis (MIC = 83.3 µg/mL), compound 4.50 was effective bactericidal agent on the strain
ACCEPTED MANUSCRIPT
Staphylococcus aureus (MIC = 20.8 µg/mL) and showed significant antifungal effect on Saccharomyces Cervesia (MIC = 41.6 µg /mL) [58]. O HN
N
N N
4.46
S
S
N
H N S
Ph
4.47 H N S
O
N
N N
H N S
S
4.48
Ph
N
N N
N N Ph
N
N
N
M AN U
4.49
N
S
O O
F
N
H N
N
N
Me
O
Ph
S 4.45
O
N N
Ph
Ph
S
N
N
O
SC
O
HN
Ph
N
RI PT
Ph
O
S 4.50
Ph
Figure 40. Antimicrobial and antifungal activity for polyheterocyclic systems based on pyrazole-
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thiazolidinones/thiazoles.
Evaluation of antimicrobial activity for thiazolidines with 5-pyrazolone fragment 4.51-4.53 (Figure 41) revealed their effectiveness on Bacillus subtilis NCTC 10400, Staphylococcus aureus
EP
ATCC 25923, Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 10415) and fungi Candida albicans TMRU 3669, Asperigillus niger ATCC 6265 [57]. O
S
N
N
Me
O
4.51
N N
Ph
Me
COOEt
O
Me
AC C
H N
N S
N N
Me
S
Me
N N
Me
O
O 4.52
H N
Me
N N Ph
4.53
N N Ph
Figure 41. Antimicrobial activity of thiazolidines/thiazoles with 5-pyrazolone fragment.
An antimicrobial screening was carried out for 3-pyrazolinyl-4-thiazolidinones against gram-positive bacteria S. aureus MTCC096, Bacillus subtilis MTCC 441 and Staphylococcus epidermis MTCC435, gram-negative bacteria Escherichia coli MTCC 443, Pseudomonas
ACCEPTED MANUSCRIPT
aeruginosa MTCC 424, Salmonella typhi MTCC 733 and Klebsiella pneumoniae MTCC 432, and antifungal effect was studied on Aspergillus niger MTCC 282, Aspergillus fumigatus MTCC 343, Aspergillus flavus MTCC 277 and Candida albicans MTCC 227. In general the tested compounds (Figure 42) showed promising antimicrobial activity. However, it could be emphasized that the bis-
Ph N O O N
Me
Ph
Me
Ph
N N
N
Me O
O
Me O
Increace of activity O
N S
(CH2)5 Br
F
4.54
O (CH2)5
N
O
N
Ph
N
Me F
4.55
M AN U
R
N
Me N N
SC
N S
RI PT
spiroindolones 4.55 showed better growth inhibition compared with compounds 4.54 [101].
Figure 42. 3-Pyrazolinyl-4-thiazolidinones with antimicrobial activity.
S.S. Reddy et al. proposed the synthesis of pyrazole-pyrimidine-thiazolidinones 4.56 (Figure
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43) and the study of their antimicrobial (Bacillus subtilis MTCC 441, Bacillus sphaericus MTCC 11, Staphylococcus aureus MTCC 96, Pseudomonas aeruginosa MTCC 741, Klobsinella aerogenes MTCC 39 and Chromobacterium violaceum MTCC 2625) and antifungal (Candida albicans ATCC
EP
10231, Aspergillus fumigatus HIC 6094, Trichophyton rubrum IFO 9185 and Trichophyton mentagrophytes IFO 40996) activities. Despite the wide range of antimicrobial research, none of
AC C
the tested compounds was more active than Penicillin (MIC = 1.56-12.5 µg/mL). The range value of the minimum inhibitory concentration was 13-30 µg/mL. However, it should be noted an antifungal activity of pyrazole-pyrimidine-thiazolidinones 4.56. The compounds with furane and 4dimethylaminophenyl-groups in position 2 of thiazolidinone showed a higher or comparable efficacy (MIC = 14-22 µg/mL) to Fluconazole [72].
ACCEPTED MANUSCRIPT Cl Me Me
Me
N
Ph N
N
O
Improved the antifungal activity
N
N
Ar N
Me
S
O
RI PT
4.56
Figure 43. Pyrazole-pyrimidine-thiazolidinones as promising antimicrobial agents.
Among 5-pyrazolyl-4-thiazolidinones the compounds 4.57 (Figure 44) were investigated for
SC
their antimicrobial activity. The most effective pyrazole-thiazolidinones included the 4-Br-phenyl
M AN U
or thiophene fragments in molecules and showed 2-4 times higher efficiency (MIC = 16-31 µg/mL) in comparison with other derivatives [80]. The moderate antimicrobial activity towards Escherichia coli and Staphylococcus aureus was identified for 3N-glycoside substituted 2-thioxo-4thiazolidinone derivatives 4.58 (Figure 44). The p-bromophenyl substituted derivative showed the highest efficiency against Escherichia coli (MIC = 143 µg/mL) but was 3 times less active than
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tetracycline (MIC = 39 µg/mL) [84].
OAc OAc
EP
Br S
AC C
Improved the antimicrobial activity
O
Ph
O
O
N
N
O Br
S
Ar
S N N Ph
4.57
N N
OAc OAc
S
4.58
Ph
Figure 44. Antimicrobial activity of 4-thiazolidinones with pyrazole in 5 position.
However, the most promising group of antimicrobial agents is 5-pyrazolylrhodanines 4.594.63 [85, 86, 102, 103]. Antimicrobial activity of these substances was studied against methicillin(MRSA) and quinolone-resistant (QRSA) Staphylococcus aureus. Compounds 4.59-4.61 exhibited stronger activity than the standard drugs, norfloxacin and oxacillin, with MIC values of 1-2 mg/mL.
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SAR analysis for pyrazole-rhodanine derivatives 4.62, 4.63 revealed the importance of aryl moiety presence in the pyrazole ring for expression of antimicrobial action and a number of substituents that considerably increased effectiveness were identified (Figure 45). HOOC N
(CH2)4 COOH
S Cl
N
S
O
N
S
S
4.59
N
1
1
N
4.61
Cl
COOH
O
N
S
Cl
Me
O
M AN U
N N Ph
R
Cl
S
S
S Me
Positions for optimization
S
O
SC
COOH
O
S
N
R
H N
N
Ph N N R = 2,4-Cl2, 4-Me 4-F, 4-Br, 4-NO2 4.60 Ph
Ph
COOH
Me
N
R
O
Ph
RI PT
O
Cl
N N
4.62
Ph
2
R
4.63
Figure 45. Structure-antimicrobial activity relationship for pyrazole-rhodanine derivatives.
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5.3. Antiviral and antiparasitic activity of pyrazole-thiazolidinone hybrids The search for new chemotherapeutic agents among pyrazole-thiazolidinones is not limited by anticancer and antimicrobial studies. The evaluation of antiviral and antiparasitic activities for
EP
mentioned hybrid compounds allowed identifying promising hit-compounds and conducting SAR analysis. Osama I. El-Sabbagh proposed the synthesis of a group of pyrazoline-thiazolidinones 4.64
AC C
and structurally related pyrazoline-thiazoles 4.65 (Figure 46) and performed a study of a wide range of antiviral activity. It should be noted that described compounds showed selective activity. However, one derivative (Ar = 4-Me-C6H4) among compounds 4.64 had moderate efficacy against herpes simplex virus type 1, herpes simplex virus type 2, vaccinia virus, vesicular stomatitis virus and thymidine kinase-deficient herpes simplex virus type 1 with value of the effective concentration of 4 µg/mL and cytotoxicity value 20 µg/mL (SI = 5) [29]. Study of thiazolidinones with sulfonamide fragment against the hepatitis C virus, conducted by Yili Ding et al. allowed to identify a number of promising antiviral agents [104]. Among the
ACCEPTED MANUSCRIPT
studied 4-thiazolidinones the pyrazole derivative 4.66 (Figure 46) showed moderate effectiveness (IC50 = 10 µg/mL and EC50 = 70 µg/mL and cytotoxicity index CC50 = 90 µg/mL). O N
N S
2
N
Ar
N
S
N N
Ar
N
1
S S
O
O
N
Ph
N H
4.66
4.65
4.64
O
Me
N Ph
O
RI PT
Ar
O
SC
Figure 46. Pyrazole/pyrazolines-thiazolidinone/thiazoles with antiviral activity.
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5-Pyrazoline substituted 4-thiazolidinones (Figure 47) were studied for their antiviral activity against SARS coronavirus (SARS CoV) and influenza types A and B viruses (Flu A, Flu B), as well as antitrypanosomal effect against Trypanosoma brucei brucei (Tbb) and Trypanosoma brucei gambiense (Tbg). Overall compounds were characterized by the similar values of anti-
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influenza viruses’ activity and cytotoxicity with selectivity indexes 1.0 to 2.1. Compound 4.68 had moderate activity against duck strain of influenza A with 50% effective concentration (EC50) 21.78 µM and selectivity index (SI) > 16.3. In general, tested compounds had no antiviral activity against
EP
SARS CoV [97]. The screening was conducted for compounds (Figure 45) against Trypanosoma brucei brucei (Tbb) and Trypanosoma brucei gambiense (Tbg). The results showed moderate
AC C
antitrypanosomal activity of compounds 4.67, 4.69 and 4.70 against both strains of tested parasites (activity indexes IC50 (Tbb) = 5.43-13.87 µM and IC50 (Tbg) = 2.53-6.66 µM) [97]. H N Ar
O
O H N
N
N
N
O
N
N S
S
O
4.68 R = OMe, Ar = 4-Me-C6H4; 4.69 R = Cl, Ar = 4-Me-C6H4; 4.70 R = Cl, Ar = 4-OMe-C6H4.
4.67
OMe
O
R
Figure 47. Antiviral and antitrypanosomal 5-pyrazoline substituted 4-thiazolidinones.
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Aiming to investigate the trypanocidal activity for pyrazoline-thiazolidinone conjugates the synthesis of new 5-(pyrazolin-1-ylmethylene)-4-thiazolidinones was carried out (Figure 48). Target heterocycles were branched by the methylidene or oxoethylamino-methylidene linker groups. The results of screening against Trypanosoma brucei gambiense allowed to identify 5 compounds with
RI PT
sufficient antitrypanosomal activity (IC50 ≤ 1.2 µM) and moderate or low cytotoxicity (CC50 = 13.6 -> 184.3 µM) towards myoblast derived cell line (L-6). Compounds 4.71 (IC50 = 0.6 µM, CC50 = 175.2 µM, SI = 292) and 4.72 (IC50 = 0.7 µM, CC50 = 40 µM, SI = 57) were significantly more
SC
effective than Nifurtimox (IC50 = 4.4 µM, 78.2 µM = CC50, SI = 17.8). SAR analysis has been directed on substitution of pyrazoline core and modification of N3-thiazolidinone position (4.73),
O N N
N
S
H N
O
O N N 2
R
2
AC C
Ar
EP
S
4.75
N Ar
N
N
S
OAc S
HO
TE D
OMe
MeO
4.72 Me
Positions for optimization
Similar level of activity
S
O
Me
N
S
4.71
M AN U
elongation of linker group (4.74) and rhodanine-isorhodanine isomerism (4.75) [98].
R
1
S
N S
Linker elongation
NH
S
N
O Decrease of activity
2
4.73
S
N O
R
N N 1
2
Ar
2
Ar 4.74
Figure 48. SAR for trypanocidal 5-(pyrazolin-1-ylmethylene)-4-thiazolidinones.
The study of antiparasitic activity for pyrazoline-thiazolidinone 4.76 (Figure 49) was carried out towars Trypanosoma cruzi, Trypanosoma b. rhodesiense, Leishmania donovani and Plasmodium falciparum. The results indicated a moderate inhibitory effect on Trypanosoma b. rhodesiense (IC50 = 12 µg/mL) and Leishmania donovani (IC50 > 30 µg/mL) and a higher influence on Plasmodium falciparum (IC50 > 5 µg/mL) with cytotoxicity index CC50 > 90 µg/mL [36].
ACCEPTED MANUSCRIPT O N S
N
Me
N Ph
4.76
RI PT
Figure 49. Pyrazoline-thiazolidinone hybrid with antiparasitic activity.
5.4. Design of new anti-inflammatory agents among pyrazole-thiazolidinones
The promising direction for pharmacological investigation of pyrazole-thiazolidinones is the search for new anti-inflammatory agents considering their structural relationship with a known
4.79,
4.80
and
thiazolidine/thiazole
derivatives
with
M AN U
pyrazoline-thiazolidine/thiazoles
SC
NSAIDs COX-2 inhibitor - celecoxib. Magda N.A. Nasr and Shehta A. Said studied a group of
hexahydroindazole fragment 4.77, 4.78 and carried out in vivo research on carrageenin induced paw edema at dose of 100 mg/kg using ketoprofen as a reference standard [105]. Results showed that pyrazoline-thiazoles/thiazolidinones 4.79, 4.80 possessed the better anti-inflammatory activity (percentage reduction of paw endema from control group was 17-50, and ketoprofen efficiency –
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63%) compared with hexahydroindazole 4.77, 4.78 analogues. Comparing the effectiveness of thiazole derivatives (4.78, 4.80) with thiazolidinones (4.77, 4.79) it could be concluded the higher
O
Ph
N
N
N
Ph
4.77
N N
Ph
S Ar 4.78
2
N
N
Ph
N
S
Ar
O
Ar
AC C
S Ar
EP
activity of pyrazoline-thiazole hybrids (39-50%) (Figure 50).
N N
Ar
1
S
N
Ar
O(S)
4.80
N
1
2
O(S)
4.79
Figure 50. Thiazolidinones and thiazoles with pyrazoline fragments as anti-inflammatory agents.
Detailed study of pyrazoline-thiazolidinones as potential COX-1 and COX-2 inhibitors allowed to identify highly active compound 4.82 (IC50 = 0.5 µM for COX-2) with the best selective index (SI = 84.8), which effectiveness was similar to that of Celecoxib. SAR analysis (Figure 51) of
ACCEPTED MANUSCRIPT
the results showed the dependence of COX-2 inhibition on the nature of aryl substituents in the 3 (A-ring) and 5 (B-ring) pyrazoline positions (structure 4.81). Thus, compounds with electron-donor substituents (methyl group) in the para- and meta-positions of the A-ring had better inhibitory effect compared with chlorine. The nature of the substituent in the para-position of the B-cycle also
RI PT
had a significant impact on the inhibitory activity of COX-2 in the order of: H > Br > Cl > F (for R1 = 3,4-Me2, 4.81); H > Me > OMe (R1 = 3,4-Cl2, 4.81) [31]. O
Me Hit-compound (IC50 = 0.5 µM for COX-2, SI = 84.8) Me
N N
S 4.82
Ph
O N
A
N
S 4.81
1
para-position is optimal
B R
R
Electron-donating substituents at paraand meta-positions are optimal
M AN U
N
SC
N
2
R2 = F < Cl < Br < H for R1 = 3,4-Me2 R2 = OMe < Me < H for R1 = 3,4-Cl2 increase of COX-2 inhibition
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Figure 51. Pyrazoline-thiazolidinone hybrids as COX-2 inhibitors.
To continue the development of structural analogues of Celecoxib, Adnan A. Bekhit et al.
EP
synthesized the series of pyrazole-thiazolidines 4.83-4.86 (Figure 52) for anti-inflammatory activity screening using cotton pellet-induced granuloma and carrageenan-induced rat paw edema
AC C
bioassays. The highly active compounds were tested for their ability to inhibit COX-1/COX-2 as well as ulcerogenic effect and acute toxicity. The first phase of the study (cotton pellet induced granuloma bioassay) allowed to establish that all compounds possessed anti-inflammatory activity with ED50 = 7.86-28.42 µM and the thiazolidine carboxylic acid derivatives (compounds 4.83 ED50 = 9.74-11.86 µM, compounds 4.84 - ED50 = 7.86-8.11 µM) showed better efficiency than Celecoxib (ED50 = 16.74 µM) and commensurable with Indomethacin (ED50 = 9.64 µM). Further studies of highly active compounds (4.83 and 4.84) allowed to identify their ability to selective
ACCEPTED MANUSCRIPT
inhibition of COX 2 (IC50 = 0.38-0.94 µM) and reaffirmed their low ulcerogenic action and acute toxicity [39]. NH2
O
Ar
N
Ar N
S
O
N
N 4.83
Ph
Ar
N
Ar
N N
S
F
O
4.84
N
Ph
N S
N
S
N
N Ph
Ph
4.85
4.86
RI PT
OH
Figure 52. Pyrazole-thiazolidine hybrids as COX-2 inhibitors.
SC
Adam M. Gilbert et al. synthesized a series of 5-pyrazolylmethylidene-2-thioxo-4thiazolidinones 4.87 (Figure 53) as potential inhibitors of ADAMTS-5 (a disintegrin and
M AN U
metalloproteinase with thrombospondin motifs 5) with significant anti-inflammatory activity. Highly active compound 4.88 was identified with the inhibition of ADAMTS-5 IC50 = 1.1 µM, that demonstrated a strong selectivity (SI > 40) compared to the inhibition of ADAMTS-4. Structural modification of substituents in the pyrazole moiety allowed to establish the main structural criteria
O
F F
4-OMe < 2-Cl < 4-t-Bu < 4-Cl
H N S
TE D
to increase the inhibitory effect [83].
O
S
F F
2
S N N 1
R
Similar level of activity
AC C
4.87
EP
R F
H N
increase of ADAMTS-5 inhibition
F N
N
S S
N N Me
S Cl
4.88
ADAMTS-5 inhibitor IC50 = 1.1 µM
Figure 53. ADAMTS-5 inhibitors among pyrazole-thiazolidinone hybrids.
Amal M. Youssef et al. carried out the synthesis of 5-((1,3-aryl-1H-pyrazol-4yl)methylene)thiazolidine-2,4-diones as potential anti-inflammatory and neuroprotective agents [79]. The studies conducted in vitro and in vivo allowed to identify a group of highly active antiinflammatory compounds with a low ulcerogenic impact and satisfactory toxicometry parameters. Based on in vitro experiments four compounds (4.89) were selected for in vivo studies according to
ACCEPTED MANUSCRIPT
screening protocols: the formalin-induced paw edema and turpentine oil-induced granuloma pouch bioassays. It was established that the tested compounds showed activity comparable to Celecoxib at a concentration of 20 mg/kg. The introduction of benzyl moiety in position 3 of thiazolidinone was accompanied by the loss of anti-inflammatory activity (Figure 54). 1
O
N O
RI PT
R
R1 =R2 = R3 = H; R1 = R3 = H, R2 = Cl; R1 = H, R2 = Cl, R3 = NO2; R1 = CH2CH=CH2, R2 = R3 = H
S
N R
3
SC
R
N
2
4.89
6. Conclusions
M AN U
Figure 54. Pyrazole-thiazolidinones with anti-inflammatory activity.
This review article presents the rational approaches to the design of chemotherapeutic agents based
on
molecular
hybridization
of
pharmacologically
attractive
thiazolidine
and
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pyrazole/pyrazoline heterocycles. Based on linkage of target heterocyclic cores the reviewed hybrids were classified as 2-, 3- and 5-pyrazole/pyrazoline-substituted thiazolidines. The basic
EP
approaches for the synthesis of pyrazole-thiazolidinones have been provided by a combination of two “small” molecules via aminolysis, acylation reactions and Knoevenagel procedure or
AC C
heterocyclization of monocyclic compounds via the [2+3]-cyclization reaction yielding the series of non-condensed bicyclic systems. The review of biological applications was focused on SAR analysis and mechanistic insights of thiazolidine-pyrazole hybrids. Molecular hybridization as a tool of medicinal chemistry has been successfully used for design of biologically active conjugates with antitumor activity, including inhibition of necroptosis, CDC25V phosphatase, TNF-α–TNFRc1 interaction or activation of pro-apoptotic BAX, antimicrobial, antifungal, antiviral and antiparasitic applications, as well as anti-inflammatory properties as inhibitors of COX or ADAMTS-5 enzymes.
ACCEPTED MANUSCRIPT
Abbreviations
a disintegrin and metalloproteinase with thrombospondin motifs
BAX
Bcl-2-associated X protein
CC50,
half maximal cytotoxic concentration
CDC25V
dual-specificity phosphatase, the “cdc” in name refers to “cell division cycle”
DCC
dicyclohexylcarbodiimide
DTP
Development Therapeutics Program
EC50
half maximal effective concentration
ED50
half maximal effective dose
IC50
half maximal inhibitory concentration
GI50
drug concentration resulting in a 50% reduction in the net protein increase in control
M AN U
SC
RI PT
ADAMTS
cells during the drug incubation HATU
1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate
minimal inhibitory concentration
MRSA
methicillin-resistant Staphylococcus aureus
MTT
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
NCI
National Cancer Institute
PIN1
peptidyl-prolyl cis-trans isomerase NIMA-interacting 1
QRSA SAR
EP
AC C
PTP1B
TE D
MIC
protein tyrosine phosphatase 1B quinolone-resistant Staphylococcus aureus
structure-activity relationships
SARS
severe acute respiratory syndrome
SI
selectivity index
Tbb
Trypanosoma brucei brucei
Tbg
Trypanosoma brucei gambiense
ACCEPTED MANUSCRIPT
drug concentration resulting in total growth inhibition
TNF-α
tumor necrosis factor alpha
TNFRc1
type-1 tumor necrosis factor receptor
VHR
Vaccinia virus H1 Related – a dual-specificity phosphatase
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RI PT
TGI
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SC
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RI PT
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Figure captions:
Figure 1. Heterocycles for pyrazole/pyrazoline-thiazole/thiazolidine hybridization and the most promising conjugates. Figure 2. Synthesis of pyrazoline-thiazolidinones via [2+3]-cyclization reactions.
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Figure 3. Three-component one-pot reactions in synthesis of 2-pyrazolinyl-4-thiazolidinones. Figure 4. Thioglycolic acid reagent in thiazolidinone ring-formation reactions.
Figure 5. Example of pyrazole formation in the synthesis of pyrazole-thiazolines.
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Figure 6. Synthesis of pyrazole-thiazolidinones with imine linker group.
Figure 7. Synthesis of diazole-thiazolidinones/thiazolidines with sulfonylimine linker group.
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Figure 8. Aminolysis reaction in synthesis of pyrazole-thiazolidinones.
Figure 9. Synthesis of pyrazole derivatives with thiazolidinone, imidazolidine and thiazoline fragments in molecules.
Figure 10. Pyrazole-substituted thiosemicarbazides in synthesis of pyrazole-thiazole hybrids. Figure 11. Synthesis of 3-diazole-substituted 4-thiazolidinones.
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Figure 12. Syntesis and modification of 3-pyrazole-substituted rhodanines. Figure 13. α-Mercaptocarboxylic acids reagent in the synthesis of 3-subtituted thiazolidinones.
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Figure 14. Holmberg synthesis for benzopyrazole-rhodanine. Figure 15. Synthesis of pyrazole-thiazolidinone conjugates via acylation reaction.
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Figure 16. Synthesis of pyrazoline-azolidinone conjugates via alkylation reaction. Figure 17. Knoevenagel and diazo coupling reactions for synthesis of pyrazole-thiazolidinones. Figure 18. Synthesis of pyrazoline-indoline-thiazolidinone conjugates. Figure 19. Synthesis of pyrazolone-thiazolidinone conjugates. Figure 20. Chromene ring-transformation reactions in synthesis of thiazolidinone-diazole hybrids. Figure 21. Synthesis of 5-pyrazole-substituted thiazolidinones via [2+3]-cyclocondensation. Figure 22. Alternative approaches for the synthesis of thiazolidinone-pyrazolones. Figure 23. Synthesis and modification of pyrazoline-thiazolidinones.
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Figure 24. Synthesis and alkylation of thiazolidinone-pyrazolines 3.16. Figure 25. Synthesis of 5-pyrazoline substituted thiazolidinones. Figure 26. Synthesis of pyrazoline-rhodanine conjugates with oxoethylamino-methylene linker group.
Figure 28. Isatin-based conjugates with antitumor activity. Figure 29. Thiazole-pyrazoline hybrids with antitumor activity.
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Figure 27. Antitumor activity for pyrazoline-thiazolidinone based hybrids.
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Figure 30. Antitumor thiazolidinone/thiazole derivatives with pyrazoline moiety in 2 position. Figure 31. Antitumor benzofuran-pyrazoles with thiazolidinone/thiazole fragments.
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Figure 32. Antitumor activity of pyrazole-thiazolidinone-triazoles on lung cancer. Figure 33. 5-Pyrazoline-substituted pseudothiohydantoines as promising necroptosis inhibitors. Figure 34. Selective antitumor activity of pyrazole-rhodanine 4.25.
Figure 35. Bis-thiazolone with indazole fragment as potential inhibitor of CDC25V phosphatase. Figure 36. Antitumor activity of 4-thiazolidinones with pyrazolines in 5 position.
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Figure 37. Pyrazoline-thiazolidinone hybrids with antimicrobial activity. Figure 38. SAR analysis of antimicrobial pyrazole-thiazolidinone hybrids.
linker group.
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Figure 39. Antimicrobial and antifungal pyrazole-thiazolidinones/thiazoles, coupled by hydrazone
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Figure 40. Antimicrobial and antifungal activity for polyheterocyclic systems based on pyrazolethiazolidinones/thiazoles.
Figure 41. Antimicrobial activity of thiazolidines/thiazoles with 5-pyrazolone fragment. Figure 42. 3-Pyrazolinyl-4-thiazolidinones with antimicrobial activity. Figure 43. Pyrazole-pyrimidine-thiazolidinones as promising antimicrobial agents. Figure 44. Antimicrobial activity of 4-thiazolidinones with pyrazole in 5 position. Figure 45. Structure-antimicrobial activity relationship for pyrazole-rhodanine derivatives. Figure 46. Pyrazole/pyrazolines-thiazolidinone/thiazoles with antiviral activity.
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Figure 47. Antiviral and antitrypanosomal 5-pyrazoline substituted 4-thiazolidinones. Figure 48. SAR for trypanocidal 5-(pyrazolin-1-ylmethylene)-4-thiazolidinones. Figure 49. Pyrazoline-thiazolidinone hybrid with antiparasitic activity. Figure 50. Thiazolidinones and thiazoles with pyrazoline fragments as anti-inflammatory agents.
Figure 52. Pyrazole-thiazolidine hybrids as COX-2 inhibitors.
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Figure 51. Pyrazoline-thiazolidinone hybrids as COX-2 inhibitors.
Figure 53. ADAMTS-5 inhibitors among pyrazole-thiazolidinone hybrids.
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Figure 54. Pyrazole-thiazolidinones with anti-inflammatory activity.
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Highlights for the manuscript “Synthetic Approaches, Structure Activity Relationship and Biological Applications for Pharmacologically Attractive Pyrazole/Pyrazoline-ThiazolidineBased Hybrids”
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by Dmytro Havrylyuk, Olexandra Roman, Roman Lesyk
Synthesis and Chemistry of Pyrazole/Pyrazoline-Thiazolidine-Based Hybrids
•
A diverse spectrum of Pyrazole/Pyrazoline-Thiazolidine-Based Hybrids biological
•
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activities has been presented.
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•
Structure activity relationship of Pyrazole/Pyrazoline-Thiazolidine-Based Hybrids for
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different activities has been discussed.
S0223-5234(16)30110-6
DOI:
10.1016/j.ejmech.2016.02.030
Reference:
EJMECH 8381
To appear in:
European Journal of Medicinal Chemistry
Received Date: 12 December 2015 Revised Date:
10 February 2016
Accepted Date: 11 February 2016
Please cite this article as: D. Havrylyuk, O. Roman, R. Lesyk, Synthetic Approaches, Structure Activity Relationship and Biological Applications for Pharmacologically Attractive Pyrazole/PyrazolineThiazolidine-Based Hybrids, European Journal of Medicinal Chemistry (2016), doi: 10.1016/ j.ejmech.2016.02.030. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. 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.
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Synthetic Approaches, Structure Activity Relationship and Biological Applications for Pharmacologically Attractive Pyrazole/Pyrazoline-Thiazolidine-Based Hybrids
N
Hybridization
H N
X
O ACTIVITY ANTITUMOR S
S O
N
N
3 ANTIMICROBIAL ACTIVITY R O
SC
N H
S
ANTIFUNGAL ACTIVITY N
N
H N
N H
S N
Hybridization
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EP
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N H
ANTIINFLAMMATORY ACTIVITY O 1 Ar N ANTIPARASITIC ACTIVITY N ANTIVIRAL ACTIVITY 2 Ar
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O
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Dmytro Havrylyuk, Olexandra Roman & Roman Lesyk
ACCEPTED MANUSCRIPT
Synthetic Approaches, Structure Activity Relationship and Biological Applications for Pharmacologically Attractive Pyrazole/Pyrazoline-Thiazolidine-Based Hybrids
Dmytro Havrylyuka,b, Olexandra Romana & Roman Lesyka,* a
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Department of Pharmaceutical, Organic and Bioorganic Chemistry
Danylo Halytsky Lviv National Medical University, 69 Pekarska Street, Lviv, 79010, Ukraine Department of Chemistry, University of Kentucky,
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505 Rose Street, Lexington, Kentucky 40506, United States
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b
*
corresponding author
[email protected], [email protected] (Roman Lesyk) tel. +38 0322 75-59-66
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fax. +38 0322 75-77-34
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Abstract: The features of the chemistry of 4-thiazolidinone and pyrazole/pyrazolines as pharmacologically attractive scaffolds were described in a number of reviews in which the main approaches to the synthesis of mentioned heterocycles and their biological activity were analyzed. However, the pyrazole/pyrazoline-thiazolidine-based hybrids as biologically active compounds is
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poorly discussed in the context of pharmacophore hybrid approach. Therefore, the purpose of this review is to summarize the data about the synthesis and modification of heterocyclic systems with thiazolidine and pyrazoline or pyrazole fragments in molecules as promising objects of modern
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analysis and mechanistic insights of mentioned hybrids.
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bioorganic and medicinal chemistry. The description of biological activity was focused on SAR
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Keywords: synthesis, biological activity, pyrazole, pyrazoline, thiazolidine.
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1. Introduction
Pharmacophore hybrid approach is a current concept in drug design and development to produce molecules with improved affinity and efficacy. There are some reviews dealing with the concept of molecular hybridization and the promises/challenges associated with these hybrid
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molecules along with recent advances on anticancer hybrids [1-3]. Various heteroaryl based hybrids in particular isatin and coumarins [3] or indoline-thiazolidinones [4] have been recently reviewed as conjugates with remarkable inhibitory potential.
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Design of new drug-like small molecules based on the pharmacologically attractive scaffolds of thiazolidine (4-thiazolidinone) [5-10] and pyrazole or pyrazoline [11-15] is a
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reasonable and promising direction in modern medicinal chemistry. The chemical approaches for the synthesis of thiazolidinone- and pyrazole-based derivatives and their pharmacological activity were described in a numerous reviews [5-12]. However, the pyrazole/pyrazoline-thiazolidine-based conjugates as biologically active compounds are poorly reviewed in the context of pharmacophore hybrid approach.
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The recent synthetic studies of pyrazole-thiazolidines and related hybrids and biological investigations for their antitumor, antimicrobial, antiviral, antiparasitic, anti-inflammatory activities to
identify
the
promising
drug-like
compounds.
Thus,
the
pyrazole-
EP
allowed
thiazolidinones/thiazoles have been patented as inhibitors of necroptosis [16], VHR protein tyrosine
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phosphatase inhibitors [17], Pin1-modulating compounds [18], compounds for modulating RNAbinding proteins [19] and activators of pro-apoptotic BAX [20]. In addition, the pyrazolethiazolidinone hybrids have been studied for their possibility to inhibit the TNF-α–TNFRc1 interaction [21], as inhibitors of histone acetyltransferases [22] and inhibitors of COX [31, 39] and ADAMTS-5 enzymes [83]. Therefore, the purpose of this review is to summarize the data about the synthesis and biological activity of heterocyclic systems with thiazolidine and pyrazole/pyrazoline fragments in molecules. The most promising pyrazole-thiazolidinone/thiazole hybrids and target heterocycles that have been reviewed as fragments of hybrid molecules are depicted in the Figure 1.
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O
Hybridization
F
Pyraz
Thiaz O
N S
O
O
H N
S
S
N H
N H
S
RNA binding proteins modulator [19]
N
Ph
N
O F
Ph
F F
O
N
S
Ph
N
S S
N N CH3
VHR protein tyrosine phosphatase inhibitor [17]
N
CH3
TNF-a inhibitor [21]
O
N N Ph
O
S
N
(CH2)nCOOH
S
SC
N
S
Pro-apoptotic BAX activator [20]
O
S
N
N H
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MeO
N
N
N H
S
N
S
CH3
O
Necroptosis inhibitor [16]
NH
CH3
H3C
N
N
N
NH
N H
N S
N
N N
N
H3C
n = 3: Pin1-modulator [18] n = 5: HAT-inhibitor [22]
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Figure 1. Heterocycles for pyrazole/pyrazoline-thiazole/thiazolidine hybridization and the most promising conjugates.
The reviewed hybrids were classified as 2-, 3- and 5-pyrazole/pyrazoline-substituted
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thiazolidines based on linkage of target heterocyclic cores. The basic approaches for the synthesis of mentioned derivatives provide a combination of two “small” molecules in aminolysis reactions, acylation and Knoevenagel procedure or heterocyclization of monocyclic compounds via the [2+3]-
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cyclization reaction yielding the series of non-condensed bicyclic systems.
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2. Synthetic approaches for 4-thiazolidinone-based hybrids with pyrazole/pyrazoline fragments in position 2.
Detailed biological activity evaluation of pyrazoline-thiazolidinone conjugates 1.2-1.7 and pyrazoline-thiazoles 1.8, 1.9 (Figure 2), synthesized via the [2+3]-cyclocondensation of 4,5dihydropyrazole-1-carbothioamides 1.1 as S,N-binucleophiles in reactions with equivalents of dielectrophilic synthon [C2]2+, allowed to identify compounds with antimicrobial [23-28], antiviral [29, 30], anti-inflammatory [31], antitumor [32-35] and insecticidal [36] activities. For synthesis of target derivatives α-halogenocarboxylic acids [31, 33] and their ethyl esters [23-29, 35, 36], maleic
ACCEPTED MANUSCRIPT
anhydride [30], maleimides [30, 38], β-aroylacrylic acids [30], dimethyl acetylenedicarboxylate [37], bromoacetophenones [23, 24, 28, 29, 35] and ethyl 4-chloroacetoacetate [35] were used as equivalents of dielectrophilic synthon [C2]2+. O
O
N N
R
O
N N
1.3 [30]
O
O
O
Ar O
R
N S
O
1.2 [23-29, 31, 33, 35, 36]
1.1 NH2
Br
O
MeO
2
Ar
N
R
N
N
1
R
O Ar O
N N
2
N
S
R
1
O
OMe
1
1.7 [37]
1.8 [35]
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R 1.9 [23, 24, 28, 29, 35]
O
S
O
O
S
S
R
1
OMe
R
N
N
1.6 [30]
OEt OEt
N
N
2
OH
O
Cl
2
O 1.5 [30, 38]
1
O
S
Ar N
1
N N
Hal = Cl, Br R = H, Et O
Ar
2
Ar N H
N
O O R
N
S
R
N
O
O
N
R
HalCH2COOR
1
R
OH
CH3CH(Br)COOH
N R
R
1
N
2
SC
2
R
S
Me
1
R
N 1.4 [30]
S R
N
2
RI PT
2
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R
N
Figure 2. Synthesis of pyrazoline-thiazolidinones via [2+3]-cyclization reactions.
EP
Three-component one-pot reaction that includes [2+3]-cyclocondensation of 4,5dihydropyrazole-1-carbotioamides 1.1 with chloroacetic acid and the further Knoevenagel reaction
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with aromatic aldehydes [33, 34] and isatin derivatives [32] is an effective approach for design of new anticancer agents among the pyrazoline-thiazolidinones 1.10, 1.11 (Figure 3).
ClCH2COOH + ArCHO
O N R
2
N N
O R R R
R
N N
O +
R ClCH2COOH
3
O N
4
R
2
N N
NH2 1.1
1.10
R
N
Ar 1
2
1
S
S
3
S N
R
1
O 1.11
Figure 3. Three-component one-pot reactions in synthesis of 2-pyrazolinyl-4-thiazolidinones.
R
4
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The reaction between pyrazolyl-imines [39, 40] or pyrazolyl-hydrazones [41] and thioglycolic acid or its esters is widely used approach for the synthesis of 4-thiazolidinone conjugates 1.12, 1.13 with pyrazole moiety in position 2. A. Khodairy proposed a synthesis of 2substituted 4-thiazolidinone with benzopyrano[2,3-c]pyrazol-3-one fragment 1.14, using N-
2
2
R
3
N
N R3
S
R
N R
N
1
OH
R
N N
Het
Het
N N H
2
O
2
O
S
1
HS R
H N N
N
N R
SC
O
RI PT
cyanoacetyl-benzopyranopyrazolone [42] as a starting compound (Figure 4).
O
R
N N
O
1
R
1.13
N
1.12
N
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O
N
O
1
R
O
N
N
1.14
S
O
N
O
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Figure 4. Thioglycolic acid reagent in thiazolidinone ring-formation reactions.
Another direction for synthesis of pyrazole-substituted thiazoline 1.16 (Figure 5) was realized by the creation of pyrazole moiety via the reaction between 5-fluoro-2-hydrazino-4-
F
NH2C(S)NHNH2
AC C
F
EP
hydroxy-4,5-bis(trifluoromethyl)-1,3-thiazoline 1.15 with acetoacetone [43, 44].
CF3
O
O CF3
OH N
CF3
S
H N
CF3
F
Me
Me CF3
OH N
CF3
S
Me N
NH2 1.15
O
F
N 1.16
Me
Figure 5. Example of pyrazole formation in the synthesis of pyrazole-thiazolines.
A broad group of pyrazole-thiazolidinone derivatives exemplified by 2-imino-4thiazolidinones (pseudothiohydantoines) 1.18, 1.19 were synthesized via [2+3]-cyclocondensation of pyrazole substituted asymmetric bis-thioureas 1.17 as S,N-binucleophiles with some equivalents of dielectrophilic synthon [C2]2+ (ethyl 2-chloroacetate [45, 46], dimethyl acetylenedicarboxylate
ACCEPTED MANUSCRIPT
[47]). Simultaneously, bioisosteric pyrazolyl-2-iminothiazolidines 1.20 [46] were obtained by reaction of thioureas 1.17 with α-bromoacetophenones (Figure 6). Het
O
R
N N
ClCH2COOEt
S
1.18
H N
H N
Het
O
S
O
MeO
OMe N
N Ar
1.19
Br
Ar R N
Het
N
Het = Ar
S
N H
N H
1.20
N
SC
N
OMe
O R
N Ar
S
Het
RI PT
N N H
N
1.17 O
Het =
O
R R
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Figure 6. Synthesis of pyrazole-thiazolidinones with imine linker group.
Aiming to search for new anticancer or antimicrobial compounds among pyrazolethiazolidinone conjugates the pyrazole-sulfonyl-thioureas 1.21 were used as starting materials. The reaction between compounds 1.21 and ethyl 2-chloroacetate or α-bromoacetophenone resulted in
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formation of the corresponding pyrazole-thiazolidinones 1.22 and pyrazole-thiazolidines 1.23 with sulfonylimine linker group [48-53] (Figure 7). O
Het
S N
AC C
SO2
EP
ClCH2COOEt
R N
1.22
1.21
Br
R Ar
R N
S
S N SO2
Het =
Me
O(S)
N
N
N
N
1
R
Het
Ar
O H N
H N SO2
Ar CF3
N
N
2
R
Het
N N
N Me
N
1
R
N N Ph
1.23
Figure 7. Synthesis of diazole-thiazolidinones/thiazolidines with sulfonylimine linker group.
Another approach for the synthesis of pyrazole derivatives of pseudothiohydantoin 1.26 was suggested by B. Insuasty et al. [54]. The synthesis of target compounds was carried out via
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aminolysis of 5-arylidene-2-thioxo-4-thiazolidinones (5-arylidenerhodanines) 1.24 by 4,5diaminopyrazoles 1.25 (Figure 8). O
H2N
H N S
Ar
N
O
+ S
Me
H N
Me
N S
N
H 2N
N
H2N
Ph 1.25
Ar
Ph 1.26
RI PT
1.24
N
Figure 8. Aminolysis reaction in synthesis of pyrazole-thiazolidinones.
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A row of 2-pyrazolyl-hydrazone-thiazolidinones 1.28-1.30 was synthesized via [2+3]cyclocondensation of thiosemicarbazones 1.27 with α-halogenocarboxylic acids derivatives or
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maleic anhydride [55-60]. The pyrazole with bioisosteric 2-thiohydantoin 1.31 [61] and thiazolidine 1.32 [55-60] fragments were obtained by reaction of thiosemicarbazones 1.27 with chloroacetic acid in pyridine or α-bromoacetophenone. However, the reaction of thiosemicarbazones 1.27 with acetic anhydride or iron chloride was accompanied by the formation of pyrazole-thiadiazole derivatives
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1.33, 1.34 [56] (Figure 9).
R
H(Me)
R
O
1
S 1.29 [55]
AC C
O
O
O
EP
OH O
Pyraz O
R
OEt
N
N
Cl
Pyraz
N
Ph N
N Pyraz 1.31 [61]
O
ClCH2COOH(Et)
O
N
ClCH2COOH
BrCH(COOEt)2 Pyraz
N
H N
H N
R
1
Ar
Ac2O Me O
S
Pyraz SO2 N H
Pyraz N Ph
S O 1.33 [56, 60]
Pyraz NH
S
1
R
1
1.34 [56]
O
N
Me N
R
H(Me)
N N
Pyraz
N N
N
N 1.32 [55-60]
FeCl3
Pyraz
1
S
1.27
N
R
N
1.28 [59]
N
1
Br
1
Me
Ar
O H(Me)
S
Me
S O
N Pyraz 1.30 [55-60] S
N
1
R
N
N
N N
1
1
Pyraz Me
Ar
Ph N N
N N
Me
Ph(Het)
Figure 9. Synthesis of pyrazole derivatives with thiazolidinone, imidazolidine and thiazoline fragments in molecules.
ACCEPTED MANUSCRIPT Pyrazole-substituted thiosemicarbazides 1.35 were used for synthesis of the pyrazolethiazolidinones 1.36 with carbohydrazide linker group [62, 63]. The three-component one-pot reaction between thiosemicarbazides 1.35, chloroacetic acid and aromatic aldehydes accompanied
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by formation of the corresponding 5-arylidene-4-thiazolidinones 1.37 [63, 64]. The modification of 1.35 in sulfuric acid medium gave pyrazole-thiadiazole 1.38 [64]. The reaction of compounds 1.35 with α-bromoacetophenones was accompanied by the formation of corresponding pyrazolethiazolidine conjugates 1.39 [62-64] (Figure 10).
N
N N H
O 1
R
Ar
N N
ClCH2COOEt
ClCH2COOH, ArCHO
S
O
Pyraz
NH
N H
O
H N
H N
N
H2SO4
1
S
N
R
S
Ar N
O
Pyraz 2
Ph 3
N
N
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R N N
H Ph N
1.36
1.35
1.37
Pyraz
S
O
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Pyraz
SC
1
R
O
R
Ar
Br
1
1
N
N N H
1.38
R
O Pyraz
Ph
N
S
Ar
1
1.39
EP
Figure 10. Pyrazole-substituted thiosemicarbazides in synthesis of pyrazole-thiazole hybrids.
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3. The main methods for synthesis of 4-thiazolidinones with pyrazole/pyrazoline moiety in position 3
Synthesis of 2-diazole-substituted 4-thiazolidinones was achieved via the [2+3]cyclocondensation of the pyrazole-based asymmetric thioureas 1.17 as S,N-binucleophiles (see Figure 6). At the same time, the numerous papers represent the data about obtaining of 4thiazolidinones with diazole moiety in 3 position (compound 2.1, Figure 11), in particular via the reaction of thioureas with ethylchloroacetate [65].
ACCEPTED MANUSCRIPT Het
H N
H N
ClCH2COOEt
Ph
Het
N N
R S
S
N
O
N H
2.1
1.17
Me
Het =
N
Me
RI PT
Figure 11. Synthesis of 3-diazole-substituted 4-thiazolidinones.
The dithiocarbamate method of 2-thioxo-4-thiazolidinones (rhodanines) synthesis is a convenient and often used variant of the synthesis of 4-thiazolidinone derivatives based on the
SC
[2+3]-cyclocondensation [5]. R.M. Mohareb et al. had successfully applied the dithiocarbamate method for the synthesis of 3-(pyrazol-5-yl)-2-thioxo-4-thiazolidinone via two-stage process based
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on the reaction between 3-phenyl-5-aminopyrazole 2.2 and carbon disulfide in an alkaline medium and subsequent cyclization with ethyl 2-bromoacetate [66]. The presence of the methylene group in the position 5 of thiazolidine cycle allowed the authors to carry out the structural modification of pyrazole-thiazolidinone 2.3 in the Knoevenagel reaction (ethanol medium, catalyst - piperidine) and
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diazotization to get the 5-substituted derivatives 2.4, 2.5. Starting from rhodanine 2.3 the alternative methods for the synthesis of condensed pyrano[2,3-d]thiazole system 2.6 with pyrazole moiety in position 3 were proposed, namely the reaction of 5-arylidenerhodanines 2.5 with malononitrile or
EP
by heterocyclization of compound 2.3 with benzylidenemalononitrile. Pyrazole-thiazolidinone 2.3 in the presence of hydrazine hydrate undergoes ring transfomation with obtaining of the pyrazole-
AC C
triazole 2.7 (Figure 12).
ACCEPTED MANUSCRIPT Ph
Ph CS2
N
NH2
N H
N
DMF, KOH
NH
N H
SK
S
2.2 Ph N
OEt
Br
S
S
+ N NCl
Ph
N
N S
2.4
N H
N
N
N
2.7
CN
PhCHO
Ph
CN
NC
Ph
Ph
CH2(CN)2 N H
S
N 2.5
Ph
Ph
O
N
M AN U
N S
SC
NH2 O
2.6
NH
HS
2.3
S
Ph
NH2NH2
Ph
O
S N
NH
O
RI PT
N
O
N
Ph
NH
S
N H
N
S
Figure 12. Syntesis and modification of 3-pyrazole-substituted rhodanines.
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Various 4-thiazolidinones were synthesized by reaction of α-mercaptocarboxylic acids (especially thioglycolic acid) with isothiocyanates (R–N=C=S). Thus, a pyrazole-thiazolidinone 2.8 with phenyl sulfonamide linker group was obtained based on the mentioned approach [67]. There
EP
were described the synthesis of 3-pyrazole-substituted or polyheterocyclic derivatives of 4thiazolidinones 2.9, 2.10 based on the reaction between thioglycolic acid and corresponding imines
AC C
and methylidene-hydrazydes or three-component reaction involving thioglycolic acid, aromatic aldehydes and heterocyclic amines containing diazole fragment [68-72]. The reaction of isatin with heterocyclic amines led to Schiff’s bases which were further reacted with thioglycolic acid to form 3-diazole-substituted indoline-spiro-thiazolidinones 2.11 [73, 74] (Figure 13).
ACCEPTED MANUSCRIPT R O
N
N
Ar
O
R
Me
N
N
N R
R
N
Ph
N
2
R
1
NH
HS
N H
R
N
O
2.11 N N
N
N H
S
N N
N H
NCS
S
NH
N
Ar
S
2.9
S
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N Ph
N
N H
O
N
O
O
O
3
R
SC
Ar
N
Ar
HN
Ph N
N
O
O
O Ac
2
R
N
O
1
1
R
3
OH
N Ph Me
N
O
R
N
N
N Ar
O
R=
N H
RI PT
S
N
2.10
or ArCHO + RNH2
O
N
N H
Ar S
Ar
H N
R=
2.8
S
Figure 13. α-Mercaptocarboxylic acids reagent in the synthesis of 3-subtituted thiazolidinones.
The reaction between trithiocarbonyl diglycolic acid and amines in alcohol or alcohol-water
TE D
medium (Holmberg synthesis) is a convenient and effective method for synthesis of 3-substituted rhodanines, especially based on the aromatic amines and carboxylic acid hydrazides [5]. The
EP
mentioned reaction was used by Augustin M. et al. for synthesis of rhodanine 2.12 with benzopyrazole fragment in position 3 [75] (Figure 14).
AC C
NH2 N
N H
OH S
+
H N
O N O
S
N S OH O
S
S 2.12
Figure 14. Holmberg synthesis for benzopyrazole-rhodanine.
The method for synthesis of pyrazole-thiazolidinone 2.15 (Figure 15) with acetamide linker group was proposed based on the reaction of 5-arylidenerhodanine-3-acetic acid 2.13 and 5-
ACCEPTED MANUSCRIPT
aminopyrazole 2.14 in DMF in the presence of HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate) [76]. 2
OH N
O
O
N N
N
N
O R1
1
R
Ar
S
S
2.14
Ar
2.15
RI PT
2.13
R
H N
N
+ HN 2
S
S
2
R
O
Figure 15. Synthesis of pyrazole-thiazolidinone conjugates via acylation reaction.
SC
Synthesis of structurally related azolidine-pyrazolines 2.16, 2.17 was proposed based on Nalkylation reaction of potassium salts of 2,4-thiazolidinedione, hydantoin and their 5-arylidene
M AN U
derivatives, obtained in situ (Figure 16). 2-Chloro-1-(3,5-diarylpyrazolin-1-yl)-ethanones were successfully used as alkylating agents [77]. 1
Ar
Ar
2
O
O
H N
N N X
O
2
1
Ar
O
Ar
O 2.16
KOH EtOH X = S, NH
Cl
O
TE D
X
O
X
2
1
Ar
Ar O
N N
3
N N
N
H N
Ar
O N
KOH EtOH
X 3
Ar
O O
2.17 X = S, NH
EP
Figure 16. Synthesis of pyrazoline-azolidinone conjugates via alkylation reaction.
4. The main approaches to the synthesis of 4-thiazolidinones with pyrazole/pyrazoline moiety
AC C
in position 5
One of the main approaches for the synthesis of 5-pyrazole/pyrazoline substituted 4thiazolidinones is based on Knoevenagel reaction of 4-thiazolidinones [5]. A numerous 1-, 3- and 5substituted pyrazole-4-carbaldehydes were used as carbonyl compounds and allowed to obtain a series of new 2,4-thiazolidinediones [78-81], rhodanines [82-86] and 2-imino-4-thiazolidinones with pyrazole moiety (compounds 3.1) [87-89]. The synthesis of pyrazolone-thiazolidinones 3.2 was
conducted
by
reaction
of
3-arylrhodanines
with
4-acetyl-5-methyl-2-phenyl-2,4-
ACCEPTED MANUSCRIPT
dihydropyrazol-3-one [90]. Position 5 of thiazolidine cycle was successfully modified in diazo coupling reaction [91] using pyrazolyl diazonium chloride yielding compound 3.3 (Figure 17). Me
H
Ar
N
N Me
O
R
5
R
N
2
R
N
O
R
N N 3 R
N N N H
5
ClPh
O
Me
H N
N N N N H
3.1
R1 = O, S, NH, N-Ar, N-N=R
SC
N
1
R
S
4
R
+
Ph
2
N
Me
3.2
R
H
R
S
Ph
O
3
1
Me N N
O
N
O
N Ph
S
S
R
RI PT
O
4
O
Me
S
S
3.3
M AN U
Figure 17. Knoevenagel and diazo coupling reactions for synthesis of pyrazole-thiazolidinones.
The synthesis of pyrazoline-indoline-thiazolidinone conjugates 3.5, 3.6 was realized by the Knoevenagel reaction of pyrazoline-isatines 3.4 with 2,4-thiazolidinedione, 2-thioxo-4-
TE D
thiazolidinone and 2-amino4-thiazolidinone in the acetic acid medium and in the presence of sodium acetate [92] (Figure 18).
R
O
3
R
O
EP
Ar
3
2
O
N Ar
1
O
K2CO3, DMF
AC C
S
X
AcONa, AcOH
R
N
N H
O
H N
O
O
N
H N
N
N
Ar
1
O
2
S
3
O N
Cl
Ar
3.4
O
O
1
3
NH2
S 2
Ar
N
N
R
AcONa, AcOH
N
N O
O N
N 1
Ar
X
Ar N
S
O 3.6
Figure 18. Synthesis of pyrazoline-indoline-thiazolidinone conjugates.
NH2
2
3.5
Ar
ACCEPTED MANUSCRIPT
The synthesis of pyrazolone-thiazolidinones 3.7 (Figure 19) was achieved based on the reaction between isonitrosorhodanines and 5-methyl-2,4-dihydropyrazol-3-one using piperidine as basic catalyst [93]. CH3 R
N S
N
HN
S N
piperidine
S
R
N
N N H
N
HO
O
O
O
RI PT
O
CH3
3.7
SC
Figure 19. Synthesis of pyrazolone-thiazolidinone conjugates.
S
Magdy Ahmed Ibrahim et al. investigated a modification of 5-[4-oxo-4H-chromen-3-
M AN U
yl)methylene]-1,3-thiazolidin-2,4-dione 3.8, in particular in the ring-transformation reactions of chromene cycle with hydrazine hydrate and phenylhydrazine. These reactions allowed to obtain the corresponding pyrazole-thiazolidinones 3.9 [94]. Using hydrazine hydrate the structure of final compounds depended on the reaction medium. Thus, 1N-non-substituted pyrazoles were obtained in
TE D
alcohol medium and in the presence of sodium ethylate, while 1N-acetylderivatives were formed in acetic acid. The reaction of the compound 3.8 and 1-phenylpyrazolidin-3,5-dione in the presence of sodium ethylate led to formation of polyheterocyclic system 3.10 (Figure 20).
O
O
EP
H N
NH2NH2 or PhNHNH2
AC C
S
N
O
O
H N
N O
R
R = H, Ph 3.9
O
H N
H N
S
O
S
Ph
O OH
N Ph
O O
N
OH
O O
3.8
N
3.10
Figure 20. Chromene ring-transformation reactions in synthesis of thiazolidinone-diazole hybrids.
Synthesis of 5-pyrazolyl-4-thiazolidinones with ethylene linker group 3.11 was performed via the [2+3]-cyclocondensation reaction of thiourea with γ-pyrazolyl-α-chlorobutanoates [95].
ACCEPTED SMANUSCRIPT
R Me
Cl
H 2N
OEt
N N
NH2
Me
H N
N
O
Me
O
R
O
S
N Me
3.11
RI PT
Figure 21. Synthesis of 5-pyrazole-substituted thiazolidinones via [2+3]-cyclocondensation.
Pharmacologically attractive 5-(5-oxo-4,5-dihydro-1H-pyrazol-4-yl)rhodanines 3.12 (Figure 22) were synthesized following heterocyclization of 2-thiazolidinyl-3-oxobutanoates with phenylhydrazine or conjugation of 4-bromopyrazolon-5-ones to 3-arylrhodanines [96].
O N
PhNHNH2
O
N
N
S
S EtO
Me
Ar
Ar
N
Ph N
S
Ph
Ar N
O
N
O
Br O
S
M AN U
Me
SC
Me
O
3.12
O
S
S
Figure 22. Alternative approaches for the synthesis of thiazolidinone-pyrazolones.
TE D
The group of pyrazoline-thiazolidinones 3.13 was obtained by reaction of 5-bromo-2,4thiazolidindione with 3,5-diarylpyrazolines in alcohol medium (Figure 23). The synthesized compounds were modified in position 3 of thiazolidine cycle by Mannich reaction with secondary
EP
cyclic amines and alkylation reactions forming 3.14, 3.15 [97]. O
2
Ar
AC C
N
H N
NH
Ar
1
Br
S
Ar
2
Ar O
N
O
N
EtOH
S
1
EtOH Ar
2
O X
N S 1
Ar
3
Ar
2
Ar
N
N
O
3.14
Figure 23. Synthesis and modification of pyrazoline-thiazolidinones.
H N Ar3
O
N
N
N
S
1
H N
Cl
O Ar
N K O
EtOH
X
N
O
3.13 HN
O
N
KOH NH
Ar
2
N
S 1
Ar
O O
3.15
ACCEPTED MANUSCRIPT The following approach to the synthesis of pyrazoline-thiazolidinone conjugates 3.16 with carbonyl methylidene linker group was based on the acylation reaction of 3,5-diarylpyrazolines (Figure 24). The further reaction of substances 3.16 with chloroacetamides via N-alkylation reaction
RI PT
led to derivatives 3.17 [97]. 3
O
H N O
S
2
Ar
O
O
1
Cl
O
Et3N, dioxane
Ar
H 3 N Ar
S
N
N
O
Ar
O
N
O
S
1
Ar
SC
NH
O
O
Cl
N
H N
HN
KOH, EtOH
O
N N
2
Ar
2
3.16
M AN U
Ar
1
Ar
3.17
Figure 24. Synthesis and alkylation of thiazolidinone-pyrazolines 3.16.
To explore the structure-antitrypanosomal activity relationship the pyrazoline-thiazolidinone
TE D
conjugates 3.18 were synthesized through the reaction of the 5-ethoxymethylidenerhodanines with 3,5-diarylpyrazolines (Figure 25). 5-Pyrazoline substituted 4-thioxo-2-thiazolidinones 3.19 were obtained under the same conditions [98].
1
R
EP
X
N
S
R N
2
Ar
Y
AC C
O
X
Ar
N H
N S
EtOH
Me
Y
N N 1
Ar
Ar
2
3.18. X = O, Y = S, R = Alk, Ar 3.19. X = S, Y = O, R = H
Figure 25. Synthesis of 5-pyrazoline substituted thiazolidinones.
To continue the above mentioned study, 5-pyrazoline derivatives of 4-thiazolidinone 3.21 with oxoethylamino-methylene linker group were synthesized by modification of rhodanine-5carboxylic acid 3.20 in the reaction with pyrazolines and in the presence of DCC (dicyclohexylcarbodiimide) [98] (Figure 26).
ACCEPTED MANUSCRIPT 1 Ar O N S O
O
Me
Me N
NH2CH2COOH S
AcOH
Me
HO
S
S
NH
N H
N
N S
S
NH
EtOH 3.20
Me
O
2
Ar
N
1
Ar
N
O
O
3.21
2
Ar
RI PT
Figure 26. Synthesis of pyrazoline-rhodanine conjugates with oxoethylamino-methylene linker group.
SC
5. Biological activity of pyrazole-thiazoldinones derivatives and reated heterocyclic hybrids 5.1. Antitumor activity of pyrazole/pyrazoline-thiazolidinone hybrids
M AN U
Antitumor activity evaluation is promising for the thiazolidinones with pyrazoline fragment. The in vitro anticancer activity of thiazolidinones with pyrazoline cycle in position 2 (4.2) or 4 (4.3) of thiazolidine was tested by the National Cancer Institute (NCI) and most of them displayed anticancer activity on leukemia, melanoma, lung, colon, CNS, ovarian, renal, prostate and breast
TE D
cancers cell lines. The most efficient anticancer compound 4.1 was found to be active with selective influence on colon cancer cell lines, especially on HT 29 (lgGI50 = -6.37) [33]. The SAR study revealed that: (1) anticancer activity of compounds is sensitive to the nature of substituent in
EP
position 5 of thiazolone cycle, (2) introduction of p-OH group in 5-benzylidene fragment enhanced potency, and (3) the positional isomers, namely 2-pyrazoline (4.2) and 4-pyrazoline (4.3)
AC C
substituted thiazolones are promising compounds for further optimization (Figure 27).
ACCEPTED MANUSCRIPT O N MeO
S OH
N HO
4.1
N OMe
pGI50 = 5.61
Ph
Ar
1
N
N
2
O
2
O
N
N
Ar
RI PT
Ar
Pyrazoline cores in positions 2 and 4 are attractive
N
N
S
S
1
3
Ar
C5-fragment (Ar3CH=) is essential
Ar
4.2
SC
4.3
Ar
3
M AN U
Figure 27. Antitumor activity for pyrazoline-thiazolidinone based hybrids.
Novel pyrazoline-thiazolidinone-isatin 4.4 and pyrazole-indoline-2-one 4.5 conjugates were designed as potential anticancer agents (Figure 28). The most effective anticancer compound 4.6 was found to be active with a mean GI50 and TGI values of 0.071 µM and 0.76 µM, respectively
TE D
and demonstrated the highest antiproliferative influence on the non-small cell lung cancer cell line HOP-92 (GI50 < 0.01 µM), colon cancer line HCT-116 (GI50 = 0.018 µM), CNS cancer cell line SNB-75 (GI50 = 0.0159 µM), ovarian cancer cell line NCI/ADR-RES (GI50 = 0.0169 µM) and renal
EP
cancer cell line RXF 393 (GI50 = 0.0197 µM). The SAR study revealed that: (1) potent anticancer activity of tested compounds depended on the presence of a combination of three heterocycles in
AC C
one molecule, thus the pyrazoline-thiazolidinone-isatin conjugates were more active in comparison with pyrazoline-thiazolidinone or pyrazole-indoline-2-one systems; (2) attachment of halogen (Br or Cl) to 5-position of isatin scaffold allowed to gain one log unit of activity (GI50 level), in comparison with 5-unsubstituted isatin analogs; (3) introduction of a methyl group or CH2COOH group at 1N-position of isatin fragment led to the loss of activity; (4) the nature of a substituent in the 5-aryl fragment also had an influence on the antitumor activity. Therefore, the introduction of electron-withdrawing group – 4-chlorine improved the antiproliferative activity in comparison with electron-donor 2-OH, 4-OMe and 4-NMe2 groups. This would indicate that decreased of electron
ACCEPTED MANUSCRIPT
density on 5-aryl moiety is important for the inhibitory activity; and (5) substitution of the phenyl fragment in 3 position of pyrazoline cycle on naphthalene-2-yl substituent did not have significant influence on antitumor activity, but introduction of the 4-methoxyphenyl group in the mentioned position limited this effect [32]. Positions for optimization
2
R
RI PT
2
R
N Ar
3
O
Significant increase of activity 1
S Ar
N N
R
N S
O
2
Ar
1
N
Significant increase of activity
R
N N Ar
4.2
1
2
Ar
4.4 O N
N H
O
1
N
N
N
O
Ar
2
4.5
M AN U
S
N
1
Ar
SC
O
N
4.6 GI50 = 0.071 µM TGI = 0.76 µM
MeO
TE D
Figure 28. Isatin-based conjugates with antitumor activity.
Y. Rajendra Prasad et al. synthesized a series of pyrazoline-thiazoles 4.7, 4.8, and examined
EP
their antitumor activity in vitro on tumor lines: Hela (human cervix carcinoma cell line), A549 (human lung adenocarcinoma cell line), MCF-7 (human breast adenocarcinoma cell line), A2780
AC C
(human ovarian cancer cell line) and BGC-823 (human gastric cancer cell line), using the MTT method. As a result of studies two hit-compounds 4.10 and 4.11 were selected. SAR analysis showed that the determining factor for exprssion of antitumor activity is the structure of the substituent in the 4 position of thiazole (Figure 29). A modification of the ester group into hydrazide and, subsequently, a hydrazone gave the potentiation of antitumor properties. At the same time, pyrazoline-thiazolidinones 4.9 had no significant cytotoxicity [35].
ACCEPTED MANUSCRIPT Ph N
N
F
H N
N
N
N
N S F
F
O
S
Positions for optimization R
N N
O
S F
Ph
N
N
Ar
N
F
R = OEt, NH-NH2, NH-N=CHAr
N
O
S F
F
F
4.8
increase of activity
N
N
S F
4.7
Ph
SC
N
4.11
IC50 (Hela) = 4.86 µM IC50 (A549) = 1.21 µM IC50 (BGC-823) = 1.20 µM
IC50 (Hela) = 4.23 µM IC50 (A549) = 0.96 µM IC50 (MCF-7) = 1.20 µM
Ph
Me
F
F
4.10
N
F
RI PT
Ph
4.9
M AN U
Figure 29. Thiazole-pyrazoline hybrids with antitumor activity.
The series of pyrazoline-thiazolidine-based compounds were tested for antitumor activity according to standard NCI protocol and 4-thiazolidinone derivatives with pyrazoline fragment 4.12,
TE D
4.14, 4.17 showed moderate cytostatic effect. The group of publications includes the synthesis of these pyrazoline-thiazolidinones 4.12, 4.14, 4.17 and pyrazoline-thiazolidines 4.13, 4.15, 4.16, 4.18 with diversity of substitution in pyrazole core. The analysis of mentioned results demonstrates that
EP
the modification of pyrazoline fragment is not crucial to the implementation of antineoplastic action
AC C
(Figure 30). This statement is evidenced by the level of efficiency of compounds 4.12-4.18 with moderate rates of effective concentration [48-51].
ACCEPTED MANUSCRIPT
Pyrazoline-thiazolidinones
Pyrazoline-thiazolidines Ph
Ph N SO2
N N
N
N SO2
N
S
Ph
N
N
O
N SO2
N
S S
4.14 GI50 = 46.8 µM
N
O N SO2
N Me
S
4.17 GI50 = 44.7 µM
O
N SO2
N
M AN U
N N
Ph
Me Ph
S
4.15 R = phenyl GI50 = 54.9 µM 4.16 R = benzoyl GI50 = 42.6 µM
SC
S
Ph
N
RI PT
N SO2
N
R
Cl
O N
S
4.13 GI50 = 41.7 µM
4.12 GI50 = 30.2 µM
Cl
Ph
N
O
N
N
Ph
S
4.18 GI50 = 20.04 µM
Me
TE D
Figure 30. Antitumor thiazolidinone/thiazole derivatives with pyrazoline moiety in 2 position.
Magdy I. El-Zahar et al [55] synthesized a group of benzofuran-pyrazoles with various heterocycles, including thiazole (4.19) and thiazolidine (4.20) fragments for screening of antitumor
EP
activity on lines: HEPG2 (liver carcinoma cell line) and HELA (cervix carcinoma cell line). Interestingly, each of these compounds showed selective effect on one of the lines similar to 5-
AC C
fluorouracil (Figure 31).
H N
O
N
O S N S
N
O
Me N N
N N Ph
Ph 4.19 GI50 = 5.0 µg/ml (HEPG2)
4.20 GI50 = 1.2 µg/ml (HEL A)
Figure 31. Antitumor benzofuran-pyrazoles with thiazolidinone/thiazole fragments.
ACCEPTED MANUSCRIPT
Synthesis and study of antitumor activity of pyrazole-thiazolidinone-triazoles on lung cancer MCF-7 line were conducted by Arun M. Isloor et al. [40]. Among the studied conjugates the compound 4.21 was the most active with the effective concentration IC50 = 22 µg/mL. The presence of o-tolyl fragment was most favorable for the anticancer effect, while substitution with naphthyl
Me
N
SH S
N
N
O
O
H N
SH
N O
N
CH3
N
N
1
R
N
S N N H
4.21 GI50 = 22 µg/ml
Cl
O R2
Increase of activity
SC
N
RI PT
ring caused complete loss of activity (Figure 32).
M AN U
Figure 32. Antitumor activity of pyrazole-thiazolidinone-triazoles on lung cancer.
An important achievement in the study of anticancer pyrazole-thiazolidinone hybrid compounds is the establishing of the necroptosis inhibition for pseudothiohydantoin derivatives
TE D
with pyrazole moiety in 5 position (Figure 33). Among these derivatives a potential inhibitor Necrostatin-7 (Nec-7) was identified with the activity index of 10.6 µM. Further studies aiming to optimize of Nec-7 molecule, were focused on the modification of thiazole fragment, replacement of
EP
substituents in the phenyl ring and replacement of pyrazole cycle by other heterocycles. It was established that the replacement of thiazole fragment by the 1,3,4-thiadiazole led to the complete
AC C
loss of activity. The introduction of the methyl group in the 4 position of thiazole caused a slight gain of inhibitory action, while presence of methyl in the 5 position of thiazole had a negative effect. The most effective direction for modification of Nec-7 was the replacement of fluorine atom in the 4 position of benzene core. Thus, the introduction of morpholine (4.22), phenol (4.23) and phenyl sulphanilic (4.24) fragments allowed to get 3-7 fold potentiation in comparison to Nec-7. In general, it should be noted that the presence of the substituent in the 4 position and its nature was crucial for the implementation of necroptosis inhibitory activity, because the change of a fluorine atom position was accompanied by loss of activity. The authors synthesized a group of related
ACCEPTED MANUSCRIPT
compounds with aromatic heterocycles (triazole and isooxazole) to establish the impact of pyrazole cycle for activity. This modification resulted in the loss of inhibitory activity, which confirmed the importance of pyrazole moiety in the analogs Nec-7 [87]. O N O
NH
O Essential heterocyclic cores
S
S
N NH
NH
N
N
N
4.22 EC50 = 2.93 µM
S
O
N
H N N
para-position is optimal
N
Ph
Ph SO2
N NH
S
4.23 EC50 = 1.29 µM
O
M AN U
F Nec-7 EC50 = 10.6 µM
N
N
N NH
S
NH
SC
N
RI PT
S
S
S
NH
4.24 EC50 = 1.78 µM
Figure 33. 5-Pyrazoline-substituted pseudothiohydantoines as promising necroptosis inhibitors.
TE D
The study of antitumor activity for pyrazole-rhodanines allowed to identify the compound 4.25, which proved effective inhibitory effect on the most of the 60 tumor lines at micromolar concentrations according to NCI protocol (Figure 34). The substance 4.25 was characterized by a
EP
selective effect on leukemia and lung cancer cell lines - especially on HOP-92 (lung cancer) with the values of effective concentration and cytotoxicity GI50 = 0.62 µM and LC50> 100 µM,
AC C
respectively [82].
Ph
O
N
N
Ph
S
4.25
NH S
CCRF-CEM (Leukemia) GI50 = 2.50 µM RPMI-8226 (Leukemia) GI50 = 2.52 µM EKVX (Non-Small Cell Lung Cancer) GI50 = 3.03 µM, NCI-H522 (Non-Small Cell Lung Cancer) GI50 = 2.96 µM HOP-92 (Non-Small Cell Lung Cancer) GI50 = 0.62 µM
Figure 34. Selective antitumor activity of pyrazole-rhodanine 4.25.
Manal Sarkis et al. carried out the synthesis of new bis-thiazolone derivatives as potential inhibitors of CDC25V phosphatase (specified enzyme involved in cell cycle progression and
ACCEPTED MANUSCRIPT
unregulated tumor development). Aiming to investigate the selectivity, the affinity of the compounds was studied to PTP1B (Protein Tyrosine Phosphatase 1B) and VHR (Vaccinia virus H1 Related – a dual-specificity phosphatase). Overall 31 compounds from bis-thiazolidinone group were synthesized and most of them displayed inhibitory activity with micromolar IC50 values lower
RI PT
than the corresponding monomers. Mentioned group of the compounds included the thiazolidinoneindazole conjugate 4.26 (Figure 35). It was established that the replacement of a 4-hydroxyphenyl fragment with indazole was accompanied by selective inhibition of CDC25B phosphatase and loss
O N
H N
O
N
N H
4.26 HO
N S
IC50 ± SEM (µM) or % of phosphatase inhibition at 100 µM CDC25B PTP1B VHR 2.9 ± 0.8 18% 25%
M AN U
S
N
SC
of PTP1B inhibitory activity (abolished PTP1B inhibition) [99].
HN
N
TE D
Figure 35. Bis-thiazolone with indazole fragment as potential inhibitor of CDC25V phosphatase.
Screening of in vitro antitumor activity for 5-pyrazoline substituted 4-thiazolidinones
EP
(compounds 4.27 and 4.28) was carried out within the DTP NCI [77, 97]. Overall tested substances had a moderate activity, but two compounds were identified with selective effect on leukemia cell
AC C
lines with effective concentration GI50 2.12-4.58 µM (4.29) and 1.64-3.20 µM (4.30). SAR analysis showed that the introduction of the linker group between heterocycles promoted the potentiation of antitumor activity, however, modification of 3N-position of thiazolidinone cycle via Mannich reaction and alkylation was not effective approach to optimization of hit-compounds (Figure 36).
2
Ar
ACCEPTED MANUSCRIPT O
O N N
N S
O
1
Modification of N3 position decreased antitumor activity
NH
2
N
S Ar
Ar
NH
O
Linker elongation increased antitumor activity
O 1
Ar
4.27
4.28
O
O
H N
H N N
S
N
N O
N
O
O
O 4.29 GI50 = 2.12 - 4.58 µM
HO
S
RI PT
MeO
4.30 GI50 = 1.64 - 3.20 µM
Cl
M AN U
SC
Figure 36. Antitumor activity of 4-thiazolidinones with pyrazolines in 5 position.
5.2. Antimicrobial and antifungal activity of pyrazoline-thiazolidinones The search for new antimicrobial and antifungal agents among pyrazoline-thiazolidinone related conjugates is a promising direction for biological testing of mentioned compounds. Mervat M. El-Enany et al. synthesized the group of 4-thiazolidinones and thiazoles with pyrazoline
TE D
fragment in 2 position and studied their antimicrobial activity against Gram-positive (Staphylococcus aureus, Bacillus subtilis), gram-negative bacteria (Escherichia coli, Pseudomonas
EP
aeruginosa) and fungi Candida albicans [24]. However, the compound 4.31 was inactive to any of the microorganisms, while activity of 4.32 on Bacillus subtilis appeared commensurate with
AC C
Amoxacillin and Propenicillin (Figure 37). The research of Bakr F. Abdel-Wahab et al. was more successful. The authors synthesized a group of triazole-pyrazoline-thiazoles and corresponding 4thiazolidinones and studied their activity against gram-positive bacteria (Staphylococcus aureus ATCC 29213, Bacillus subtilis ATCC6633, Bacillus megaterium ATCC 9885, Sarcina lutea), gram-negative
bacteria
(Klebseilla
pneumonia
ATCC13883,
Pseudomonas
aeroginosa
ATCC27953, Escherichia coli ATCC 25922) and fungi (Saccharomyces cerevisiae and Candida albicans NRRL Y-477) compared with Ciprofloxacin and Ketoconazole [23]. Among the tested thiazole-pyrazolines compound 4.33 showed the highest activity for strain Pseudomonas
ACCEPTED MANUSCRIPT
aeroginosa (MIC = 8.25 µg/mL), which was twice higher than for Ciprofloxacin. Activity of 4.34 appeared commensurate with the drug for bacteria Staphylococcus aureus and Bacillus subtilis (MIC = 8.25 µg/mL). At the same time 4.35 showed a high antifungal activity (MIC = 8.25 µg/mL). It should be noted that the replacement of thiazole fragment with the 4-thiazolidinone was
RI PT
accompanied by the loss of antimicrobial activity against most types of bacteria and fungi, but compound 4.36 showed the highest activity in Bacillus megaterium and Escherichia coli, which were much less sensitive to the action of thiazole-pyrazolines (Figure 37). Study of antimicrobial
SC
activity for structurally related quinoline-pyrazoline-thiazolidones 4.37 against strains Escherichia coli (MTCC 443), Pseudomonas aeruginosa (MTCC 1688), Staphylococcus aureus (MTCC 96),
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Streptococcus pyogenes (MTCC 442) and antifungal effect on Candida albicans (MTCC 227), Aspergillus niger (MTCC 282) and Aspergillus clavatus (MTCC 1323) evidenced of their minor or moderate activity on most types of microorganisms with MIC values range = 50-500 µg/mL [25]. However, among the above groups of compounds 4.38 could be selected, which showed 2-8 times higher bactericidal activity in experiment than Ampicillin and was twice active than Griseofulvin on
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fungi. The mentioned compound showed the highest activity with the value of MIC 12.5 µg/mL to Pseudomonas aeruginosa (Figure 37). Cl
EP
Cl
Br
AC C
N
F
R
S Cl
N
N
N
N S
Br
4.31
O
4.32
S
F
N N
N N
N
N N
N
Br N N
4.33 R = H, 4.34 R = Cl, 4.35 R = Br
Me
O
Me
N
N N
N
Me
S
4.36
Me
Cl
N
Ar Me
N N O
S
+
N N
Me
N
O
N
4.37 O
S
Figure 37. Pyrazoline-thiazolidinone hybrids with antimicrobial activity.
4.38
N
O
ACCEPTED MANUSCRIPT C.S. Reddy et al. performed the synthesis and study of antimicrobial activity of thiazolidinone-pyrazoles 4.39 against the Bacillus subtilis, Staphylococcus aureus, Escherichia coli and Staphylococcus pyogenes. It was established the moderate effect of mentioned compounds
RI PT
(MIC = 6.25-50 µg/mL) (Figure 38). The introduction of chlorine, nitro or hydroxyl groups in the para-position of the benzene ring resulted in 2-4 fold potentiation of activity in comparison to 3phenyl-4-thiazolidinones. However, replacement of the phenyl moiety to pyridine (4.40) or
R
increase of activity
Me N
Ph
Me
N
S
N 4.39
Me
O
N
N S
N
M AN U
O
Me < Cl-, NO2 or OH
SC
pyrimidine was particularly effective, which allowed to get 4-8 fold enhance of efficiency [100].
Ph
N Me
4.40
TE D
Figure 38. SAR analysis of antimicrobial pyrazole-thiazolidinone hybrids.
The pyrazole-thiazolidinones 4.41 or pyrazole-thiazoles 4.42, coupled by hydrazone linker group were investigated as promising agents with antimicrobial and antifungal activity. It was found
EP
that the compound 4.41b (R = Me) showed comparable activity (MIC = 25 µg/mL) with Ampicillin
AC C
against E. coli, and the compound 4.41c (R = Cl) appeared to be the most active on C. albicans (MIC = 12.5 µg/mL) (Figure 39). Overall, pyrazole-thiazolidinones 4.41 had higher activity than related pyrazole-thiazoles 4.42 [60]. Adnan A. Bekhit et al. synthesized the pyrazoline-thiazoles and thiazolidinones with sulfanilamide group. Among the studied pyrazole-thiazolidinones 4.43 and pyrazole-thiazoles 4.44 the compounds 4.43b (R = Me) and 4.44a (R = H) (Figure 39) were most effective against E. coli (MIC = 25 µg/mL) [56].
ACCEPTED MANUSCRIPT R
R
Br
Br N
Ph
N
N 4.41
N
S
N
S
S
N
N
N
N
Ph Ph
4.42
Ph
R = H (a), Me (b), Cl (c)
Ph
N
N
O
N
S O
N
N N Me
N
S
N
S 4.43
S O
Me Br
SC
N
O
N
O
N N
N
R
N
R
RI PT
O
S
N
Me
Me
4.44
M AN U
Figure 39. Antimicrobial and antifungal pyrazole-thiazolidinones/thiazoles, coupled by hydrazone linker group.
The study of wide range of antimicrobial and antifungal activities of new benzofuranyl-
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pyrazoles with thiazolidinone fragment was conducted by Bakr F. Abdel-Wahab et al. The compound 4.45 showed activity against C. albicans and Bacillus subitilis, and thiazole-derivative 4.46 was effective against the E. coli [62] (Figure 40). To continue the research of pyrazole
EP
derivatives with different heterocycles, authors conducted the synthesis of new derivatives of pyrazole with thiophene fragment 4.47-4.49, including pyrazole-thiazolidine 4.50 (Figure 40) and
AC C
offered a wide range of biological studies, including the evaluation of antimicrobial activity against the following microorganisms: Staphylococcus aureus ATCC 29213, B. subtilis ATCC6633, Salmonella typhi, Enterobacter Cloaca ATCC3047, Klebseilla peneumoniae ATCC13883, Pseudomonas. aeroginosa ATCC27953, E. coli ATCC 25922, Enterococcus faecalis ATCC29212, Mycobacterium phlei, Saccharomyces Cervesia and Candida Albicans NRRL Y-477. Among the tested compounds 4.47 and 4.49 showed hihg/good or moderate efficiency against all strains of microorganisms. While compound 4.48 had proved to be the most effective on Enterococcus faecalis (MIC = 83.3 µg/mL), compound 4.50 was effective bactericidal agent on the strain
ACCEPTED MANUSCRIPT
Staphylococcus aureus (MIC = 20.8 µg/mL) and showed significant antifungal effect on Saccharomyces Cervesia (MIC = 41.6 µg /mL) [58]. O HN
N
N N
4.46
S
S
N
H N S
Ph
4.47 H N S
O
N
N N
H N S
S
4.48
Ph
N
N N
N N Ph
N
N
N
M AN U
4.49
N
S
O O
F
N
H N
N
N
Me
O
Ph
S 4.45
O
N N
Ph
Ph
S
N
N
O
SC
O
HN
Ph
N
RI PT
Ph
O
S 4.50
Ph
Figure 40. Antimicrobial and antifungal activity for polyheterocyclic systems based on pyrazole-
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thiazolidinones/thiazoles.
Evaluation of antimicrobial activity for thiazolidines with 5-pyrazolone fragment 4.51-4.53 (Figure 41) revealed their effectiveness on Bacillus subtilis NCTC 10400, Staphylococcus aureus
EP
ATCC 25923, Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 10415) and fungi Candida albicans TMRU 3669, Asperigillus niger ATCC 6265 [57]. O
S
N
N
Me
O
4.51
N N
Ph
Me
COOEt
O
Me
AC C
H N
N S
N N
Me
S
Me
N N
Me
O
O 4.52
H N
Me
N N Ph
4.53
N N Ph
Figure 41. Antimicrobial activity of thiazolidines/thiazoles with 5-pyrazolone fragment.
An antimicrobial screening was carried out for 3-pyrazolinyl-4-thiazolidinones against gram-positive bacteria S. aureus MTCC096, Bacillus subtilis MTCC 441 and Staphylococcus epidermis MTCC435, gram-negative bacteria Escherichia coli MTCC 443, Pseudomonas
ACCEPTED MANUSCRIPT
aeruginosa MTCC 424, Salmonella typhi MTCC 733 and Klebsiella pneumoniae MTCC 432, and antifungal effect was studied on Aspergillus niger MTCC 282, Aspergillus fumigatus MTCC 343, Aspergillus flavus MTCC 277 and Candida albicans MTCC 227. In general the tested compounds (Figure 42) showed promising antimicrobial activity. However, it could be emphasized that the bis-
Ph N O O N
Me
Ph
Me
Ph
N N
N
Me O
O
Me O
Increace of activity O
N S
(CH2)5 Br
F
4.54
O (CH2)5
N
O
N
Ph
N
Me F
4.55
M AN U
R
N
Me N N
SC
N S
RI PT
spiroindolones 4.55 showed better growth inhibition compared with compounds 4.54 [101].
Figure 42. 3-Pyrazolinyl-4-thiazolidinones with antimicrobial activity.
S.S. Reddy et al. proposed the synthesis of pyrazole-pyrimidine-thiazolidinones 4.56 (Figure
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43) and the study of their antimicrobial (Bacillus subtilis MTCC 441, Bacillus sphaericus MTCC 11, Staphylococcus aureus MTCC 96, Pseudomonas aeruginosa MTCC 741, Klobsinella aerogenes MTCC 39 and Chromobacterium violaceum MTCC 2625) and antifungal (Candida albicans ATCC
EP
10231, Aspergillus fumigatus HIC 6094, Trichophyton rubrum IFO 9185 and Trichophyton mentagrophytes IFO 40996) activities. Despite the wide range of antimicrobial research, none of
AC C
the tested compounds was more active than Penicillin (MIC = 1.56-12.5 µg/mL). The range value of the minimum inhibitory concentration was 13-30 µg/mL. However, it should be noted an antifungal activity of pyrazole-pyrimidine-thiazolidinones 4.56. The compounds with furane and 4dimethylaminophenyl-groups in position 2 of thiazolidinone showed a higher or comparable efficacy (MIC = 14-22 µg/mL) to Fluconazole [72].
ACCEPTED MANUSCRIPT Cl Me Me
Me
N
Ph N
N
O
Improved the antifungal activity
N
N
Ar N
Me
S
O
RI PT
4.56
Figure 43. Pyrazole-pyrimidine-thiazolidinones as promising antimicrobial agents.
Among 5-pyrazolyl-4-thiazolidinones the compounds 4.57 (Figure 44) were investigated for
SC
their antimicrobial activity. The most effective pyrazole-thiazolidinones included the 4-Br-phenyl
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or thiophene fragments in molecules and showed 2-4 times higher efficiency (MIC = 16-31 µg/mL) in comparison with other derivatives [80]. The moderate antimicrobial activity towards Escherichia coli and Staphylococcus aureus was identified for 3N-glycoside substituted 2-thioxo-4thiazolidinone derivatives 4.58 (Figure 44). The p-bromophenyl substituted derivative showed the highest efficiency against Escherichia coli (MIC = 143 µg/mL) but was 3 times less active than
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tetracycline (MIC = 39 µg/mL) [84].
OAc OAc
EP
Br S
AC C
Improved the antimicrobial activity
O
Ph
O
O
N
N
O Br
S
Ar
S N N Ph
4.57
N N
OAc OAc
S
4.58
Ph
Figure 44. Antimicrobial activity of 4-thiazolidinones with pyrazole in 5 position.
However, the most promising group of antimicrobial agents is 5-pyrazolylrhodanines 4.594.63 [85, 86, 102, 103]. Antimicrobial activity of these substances was studied against methicillin(MRSA) and quinolone-resistant (QRSA) Staphylococcus aureus. Compounds 4.59-4.61 exhibited stronger activity than the standard drugs, norfloxacin and oxacillin, with MIC values of 1-2 mg/mL.
ACCEPTED MANUSCRIPT
SAR analysis for pyrazole-rhodanine derivatives 4.62, 4.63 revealed the importance of aryl moiety presence in the pyrazole ring for expression of antimicrobial action and a number of substituents that considerably increased effectiveness were identified (Figure 45). HOOC N
(CH2)4 COOH
S Cl
N
S
O
N
S
S
4.59
N
1
1
N
4.61
Cl
COOH
O
N
S
Cl
Me
O
M AN U
N N Ph
R
Cl
S
S
S Me
Positions for optimization
S
O
SC
COOH
O
S
N
R
H N
N
Ph N N R = 2,4-Cl2, 4-Me 4-F, 4-Br, 4-NO2 4.60 Ph
Ph
COOH
Me
N
R
O
Ph
RI PT
O
Cl
N N
4.62
Ph
2
R
4.63
Figure 45. Structure-antimicrobial activity relationship for pyrazole-rhodanine derivatives.
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5.3. Antiviral and antiparasitic activity of pyrazole-thiazolidinone hybrids The search for new chemotherapeutic agents among pyrazole-thiazolidinones is not limited by anticancer and antimicrobial studies. The evaluation of antiviral and antiparasitic activities for
EP
mentioned hybrid compounds allowed identifying promising hit-compounds and conducting SAR analysis. Osama I. El-Sabbagh proposed the synthesis of a group of pyrazoline-thiazolidinones 4.64
AC C
and structurally related pyrazoline-thiazoles 4.65 (Figure 46) and performed a study of a wide range of antiviral activity. It should be noted that described compounds showed selective activity. However, one derivative (Ar = 4-Me-C6H4) among compounds 4.64 had moderate efficacy against herpes simplex virus type 1, herpes simplex virus type 2, vaccinia virus, vesicular stomatitis virus and thymidine kinase-deficient herpes simplex virus type 1 with value of the effective concentration of 4 µg/mL and cytotoxicity value 20 µg/mL (SI = 5) [29]. Study of thiazolidinones with sulfonamide fragment against the hepatitis C virus, conducted by Yili Ding et al. allowed to identify a number of promising antiviral agents [104]. Among the
ACCEPTED MANUSCRIPT
studied 4-thiazolidinones the pyrazole derivative 4.66 (Figure 46) showed moderate effectiveness (IC50 = 10 µg/mL and EC50 = 70 µg/mL and cytotoxicity index CC50 = 90 µg/mL). O N
N S
2
N
Ar
N
S
N N
Ar
N
1
S S
O
O
N
Ph
N H
4.66
4.65
4.64
O
Me
N Ph
O
RI PT
Ar
O
SC
Figure 46. Pyrazole/pyrazolines-thiazolidinone/thiazoles with antiviral activity.
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5-Pyrazoline substituted 4-thiazolidinones (Figure 47) were studied for their antiviral activity against SARS coronavirus (SARS CoV) and influenza types A and B viruses (Flu A, Flu B), as well as antitrypanosomal effect against Trypanosoma brucei brucei (Tbb) and Trypanosoma brucei gambiense (Tbg). Overall compounds were characterized by the similar values of anti-
TE D
influenza viruses’ activity and cytotoxicity with selectivity indexes 1.0 to 2.1. Compound 4.68 had moderate activity against duck strain of influenza A with 50% effective concentration (EC50) 21.78 µM and selectivity index (SI) > 16.3. In general, tested compounds had no antiviral activity against
EP
SARS CoV [97]. The screening was conducted for compounds (Figure 45) against Trypanosoma brucei brucei (Tbb) and Trypanosoma brucei gambiense (Tbg). The results showed moderate
AC C
antitrypanosomal activity of compounds 4.67, 4.69 and 4.70 against both strains of tested parasites (activity indexes IC50 (Tbb) = 5.43-13.87 µM and IC50 (Tbg) = 2.53-6.66 µM) [97]. H N Ar
O
O H N
N
N
N
O
N
N S
S
O
4.68 R = OMe, Ar = 4-Me-C6H4; 4.69 R = Cl, Ar = 4-Me-C6H4; 4.70 R = Cl, Ar = 4-OMe-C6H4.
4.67
OMe
O
R
Figure 47. Antiviral and antitrypanosomal 5-pyrazoline substituted 4-thiazolidinones.
ACCEPTED MANUSCRIPT
Aiming to investigate the trypanocidal activity for pyrazoline-thiazolidinone conjugates the synthesis of new 5-(pyrazolin-1-ylmethylene)-4-thiazolidinones was carried out (Figure 48). Target heterocycles were branched by the methylidene or oxoethylamino-methylidene linker groups. The results of screening against Trypanosoma brucei gambiense allowed to identify 5 compounds with
RI PT
sufficient antitrypanosomal activity (IC50 ≤ 1.2 µM) and moderate or low cytotoxicity (CC50 = 13.6 -> 184.3 µM) towards myoblast derived cell line (L-6). Compounds 4.71 (IC50 = 0.6 µM, CC50 = 175.2 µM, SI = 292) and 4.72 (IC50 = 0.7 µM, CC50 = 40 µM, SI = 57) were significantly more
SC
effective than Nifurtimox (IC50 = 4.4 µM, 78.2 µM = CC50, SI = 17.8). SAR analysis has been directed on substitution of pyrazoline core and modification of N3-thiazolidinone position (4.73),
O N N
N
S
H N
O
O N N 2
R
2
AC C
Ar
EP
S
4.75
N Ar
N
N
S
OAc S
HO
TE D
OMe
MeO
4.72 Me
Positions for optimization
Similar level of activity
S
O
Me
N
S
4.71
M AN U
elongation of linker group (4.74) and rhodanine-isorhodanine isomerism (4.75) [98].
R
1
S
N S
Linker elongation
NH
S
N
O Decrease of activity
2
4.73
S
N O
R
N N 1
2
Ar
2
Ar 4.74
Figure 48. SAR for trypanocidal 5-(pyrazolin-1-ylmethylene)-4-thiazolidinones.
The study of antiparasitic activity for pyrazoline-thiazolidinone 4.76 (Figure 49) was carried out towars Trypanosoma cruzi, Trypanosoma b. rhodesiense, Leishmania donovani and Plasmodium falciparum. The results indicated a moderate inhibitory effect on Trypanosoma b. rhodesiense (IC50 = 12 µg/mL) and Leishmania donovani (IC50 > 30 µg/mL) and a higher influence on Plasmodium falciparum (IC50 > 5 µg/mL) with cytotoxicity index CC50 > 90 µg/mL [36].
ACCEPTED MANUSCRIPT O N S
N
Me
N Ph
4.76
RI PT
Figure 49. Pyrazoline-thiazolidinone hybrid with antiparasitic activity.
5.4. Design of new anti-inflammatory agents among pyrazole-thiazolidinones
The promising direction for pharmacological investigation of pyrazole-thiazolidinones is the search for new anti-inflammatory agents considering their structural relationship with a known
4.79,
4.80
and
thiazolidine/thiazole
derivatives
with
M AN U
pyrazoline-thiazolidine/thiazoles
SC
NSAIDs COX-2 inhibitor - celecoxib. Magda N.A. Nasr and Shehta A. Said studied a group of
hexahydroindazole fragment 4.77, 4.78 and carried out in vivo research on carrageenin induced paw edema at dose of 100 mg/kg using ketoprofen as a reference standard [105]. Results showed that pyrazoline-thiazoles/thiazolidinones 4.79, 4.80 possessed the better anti-inflammatory activity (percentage reduction of paw endema from control group was 17-50, and ketoprofen efficiency –
TE D
63%) compared with hexahydroindazole 4.77, 4.78 analogues. Comparing the effectiveness of thiazole derivatives (4.78, 4.80) with thiazolidinones (4.77, 4.79) it could be concluded the higher
O
Ph
N
N
N
Ph
4.77
N N
Ph
S Ar 4.78
2
N
N
Ph
N
S
Ar
O
Ar
AC C
S Ar
EP
activity of pyrazoline-thiazole hybrids (39-50%) (Figure 50).
N N
Ar
1
S
N
Ar
O(S)
4.80
N
1
2
O(S)
4.79
Figure 50. Thiazolidinones and thiazoles with pyrazoline fragments as anti-inflammatory agents.
Detailed study of pyrazoline-thiazolidinones as potential COX-1 and COX-2 inhibitors allowed to identify highly active compound 4.82 (IC50 = 0.5 µM for COX-2) with the best selective index (SI = 84.8), which effectiveness was similar to that of Celecoxib. SAR analysis (Figure 51) of
ACCEPTED MANUSCRIPT
the results showed the dependence of COX-2 inhibition on the nature of aryl substituents in the 3 (A-ring) and 5 (B-ring) pyrazoline positions (structure 4.81). Thus, compounds with electron-donor substituents (methyl group) in the para- and meta-positions of the A-ring had better inhibitory effect compared with chlorine. The nature of the substituent in the para-position of the B-cycle also
RI PT
had a significant impact on the inhibitory activity of COX-2 in the order of: H > Br > Cl > F (for R1 = 3,4-Me2, 4.81); H > Me > OMe (R1 = 3,4-Cl2, 4.81) [31]. O
Me Hit-compound (IC50 = 0.5 µM for COX-2, SI = 84.8) Me
N N
S 4.82
Ph
O N
A
N
S 4.81
1
para-position is optimal
B R
R
Electron-donating substituents at paraand meta-positions are optimal
M AN U
N
SC
N
2
R2 = F < Cl < Br < H for R1 = 3,4-Me2 R2 = OMe < Me < H for R1 = 3,4-Cl2 increase of COX-2 inhibition
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Figure 51. Pyrazoline-thiazolidinone hybrids as COX-2 inhibitors.
To continue the development of structural analogues of Celecoxib, Adnan A. Bekhit et al.
EP
synthesized the series of pyrazole-thiazolidines 4.83-4.86 (Figure 52) for anti-inflammatory activity screening using cotton pellet-induced granuloma and carrageenan-induced rat paw edema
AC C
bioassays. The highly active compounds were tested for their ability to inhibit COX-1/COX-2 as well as ulcerogenic effect and acute toxicity. The first phase of the study (cotton pellet induced granuloma bioassay) allowed to establish that all compounds possessed anti-inflammatory activity with ED50 = 7.86-28.42 µM and the thiazolidine carboxylic acid derivatives (compounds 4.83 ED50 = 9.74-11.86 µM, compounds 4.84 - ED50 = 7.86-8.11 µM) showed better efficiency than Celecoxib (ED50 = 16.74 µM) and commensurable with Indomethacin (ED50 = 9.64 µM). Further studies of highly active compounds (4.83 and 4.84) allowed to identify their ability to selective
ACCEPTED MANUSCRIPT
inhibition of COX 2 (IC50 = 0.38-0.94 µM) and reaffirmed their low ulcerogenic action and acute toxicity [39]. NH2
O
Ar
N
Ar N
S
O
N
N 4.83
Ph
Ar
N
Ar
N N
S
F
O
4.84
N
Ph
N S
N
S
N
N Ph
Ph
4.85
4.86
RI PT
OH
Figure 52. Pyrazole-thiazolidine hybrids as COX-2 inhibitors.
SC
Adam M. Gilbert et al. synthesized a series of 5-pyrazolylmethylidene-2-thioxo-4thiazolidinones 4.87 (Figure 53) as potential inhibitors of ADAMTS-5 (a disintegrin and
M AN U
metalloproteinase with thrombospondin motifs 5) with significant anti-inflammatory activity. Highly active compound 4.88 was identified with the inhibition of ADAMTS-5 IC50 = 1.1 µM, that demonstrated a strong selectivity (SI > 40) compared to the inhibition of ADAMTS-4. Structural modification of substituents in the pyrazole moiety allowed to establish the main structural criteria
O
F F
4-OMe < 2-Cl < 4-t-Bu < 4-Cl
H N S
TE D
to increase the inhibitory effect [83].
O
S
F F
2
S N N 1
R
Similar level of activity
AC C
4.87
EP
R F
H N
increase of ADAMTS-5 inhibition
F N
N
S S
N N Me
S Cl
4.88
ADAMTS-5 inhibitor IC50 = 1.1 µM
Figure 53. ADAMTS-5 inhibitors among pyrazole-thiazolidinone hybrids.
Amal M. Youssef et al. carried out the synthesis of 5-((1,3-aryl-1H-pyrazol-4yl)methylene)thiazolidine-2,4-diones as potential anti-inflammatory and neuroprotective agents [79]. The studies conducted in vitro and in vivo allowed to identify a group of highly active antiinflammatory compounds with a low ulcerogenic impact and satisfactory toxicometry parameters. Based on in vitro experiments four compounds (4.89) were selected for in vivo studies according to
ACCEPTED MANUSCRIPT
screening protocols: the formalin-induced paw edema and turpentine oil-induced granuloma pouch bioassays. It was established that the tested compounds showed activity comparable to Celecoxib at a concentration of 20 mg/kg. The introduction of benzyl moiety in position 3 of thiazolidinone was accompanied by the loss of anti-inflammatory activity (Figure 54). 1
O
N O
RI PT
R
R1 =R2 = R3 = H; R1 = R3 = H, R2 = Cl; R1 = H, R2 = Cl, R3 = NO2; R1 = CH2CH=CH2, R2 = R3 = H
S
N R
3
SC
R
N
2
4.89
6. Conclusions
M AN U
Figure 54. Pyrazole-thiazolidinones with anti-inflammatory activity.
This review article presents the rational approaches to the design of chemotherapeutic agents based
on
molecular
hybridization
of
pharmacologically
attractive
thiazolidine
and
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pyrazole/pyrazoline heterocycles. Based on linkage of target heterocyclic cores the reviewed hybrids were classified as 2-, 3- and 5-pyrazole/pyrazoline-substituted thiazolidines. The basic
EP
approaches for the synthesis of pyrazole-thiazolidinones have been provided by a combination of two “small” molecules via aminolysis, acylation reactions and Knoevenagel procedure or
AC C
heterocyclization of monocyclic compounds via the [2+3]-cyclization reaction yielding the series of non-condensed bicyclic systems. The review of biological applications was focused on SAR analysis and mechanistic insights of thiazolidine-pyrazole hybrids. Molecular hybridization as a tool of medicinal chemistry has been successfully used for design of biologically active conjugates with antitumor activity, including inhibition of necroptosis, CDC25V phosphatase, TNF-α–TNFRc1 interaction or activation of pro-apoptotic BAX, antimicrobial, antifungal, antiviral and antiparasitic applications, as well as anti-inflammatory properties as inhibitors of COX or ADAMTS-5 enzymes.
ACCEPTED MANUSCRIPT
Abbreviations
a disintegrin and metalloproteinase with thrombospondin motifs
BAX
Bcl-2-associated X protein
CC50,
half maximal cytotoxic concentration
CDC25V
dual-specificity phosphatase, the “cdc” in name refers to “cell division cycle”
DCC
dicyclohexylcarbodiimide
DTP
Development Therapeutics Program
EC50
half maximal effective concentration
ED50
half maximal effective dose
IC50
half maximal inhibitory concentration
GI50
drug concentration resulting in a 50% reduction in the net protein increase in control
M AN U
SC
RI PT
ADAMTS
cells during the drug incubation HATU
1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate
minimal inhibitory concentration
MRSA
methicillin-resistant Staphylococcus aureus
MTT
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
NCI
National Cancer Institute
PIN1
peptidyl-prolyl cis-trans isomerase NIMA-interacting 1
QRSA SAR
EP
AC C
PTP1B
TE D
MIC
protein tyrosine phosphatase 1B quinolone-resistant Staphylococcus aureus
structure-activity relationships
SARS
severe acute respiratory syndrome
SI
selectivity index
Tbb
Trypanosoma brucei brucei
Tbg
Trypanosoma brucei gambiense
ACCEPTED MANUSCRIPT
drug concentration resulting in total growth inhibition
TNF-α
tumor necrosis factor alpha
TNFRc1
type-1 tumor necrosis factor receptor
VHR
Vaccinia virus H1 Related – a dual-specificity phosphatase
References
RI PT
TGI
1. S. Fortin, G. Berube, Advances in the development of hybrid anticancer drugs, Expert Opin.
SC
Drug Discov. 8 (2013) 1547 - 1577.
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Figure captions:
Figure 1. Heterocycles for pyrazole/pyrazoline-thiazole/thiazolidine hybridization and the most promising conjugates. Figure 2. Synthesis of pyrazoline-thiazolidinones via [2+3]-cyclization reactions.
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Figure 3. Three-component one-pot reactions in synthesis of 2-pyrazolinyl-4-thiazolidinones. Figure 4. Thioglycolic acid reagent in thiazolidinone ring-formation reactions.
Figure 5. Example of pyrazole formation in the synthesis of pyrazole-thiazolines.
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Figure 6. Synthesis of pyrazole-thiazolidinones with imine linker group.
Figure 7. Synthesis of diazole-thiazolidinones/thiazolidines with sulfonylimine linker group.
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Figure 8. Aminolysis reaction in synthesis of pyrazole-thiazolidinones.
Figure 9. Synthesis of pyrazole derivatives with thiazolidinone, imidazolidine and thiazoline fragments in molecules.
Figure 10. Pyrazole-substituted thiosemicarbazides in synthesis of pyrazole-thiazole hybrids. Figure 11. Synthesis of 3-diazole-substituted 4-thiazolidinones.
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Figure 12. Syntesis and modification of 3-pyrazole-substituted rhodanines. Figure 13. α-Mercaptocarboxylic acids reagent in the synthesis of 3-subtituted thiazolidinones.
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Figure 14. Holmberg synthesis for benzopyrazole-rhodanine. Figure 15. Synthesis of pyrazole-thiazolidinone conjugates via acylation reaction.
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Figure 16. Synthesis of pyrazoline-azolidinone conjugates via alkylation reaction. Figure 17. Knoevenagel and diazo coupling reactions for synthesis of pyrazole-thiazolidinones. Figure 18. Synthesis of pyrazoline-indoline-thiazolidinone conjugates. Figure 19. Synthesis of pyrazolone-thiazolidinone conjugates. Figure 20. Chromene ring-transformation reactions in synthesis of thiazolidinone-diazole hybrids. Figure 21. Synthesis of 5-pyrazole-substituted thiazolidinones via [2+3]-cyclocondensation. Figure 22. Alternative approaches for the synthesis of thiazolidinone-pyrazolones. Figure 23. Synthesis and modification of pyrazoline-thiazolidinones.
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Figure 24. Synthesis and alkylation of thiazolidinone-pyrazolines 3.16. Figure 25. Synthesis of 5-pyrazoline substituted thiazolidinones. Figure 26. Synthesis of pyrazoline-rhodanine conjugates with oxoethylamino-methylene linker group.
Figure 28. Isatin-based conjugates with antitumor activity. Figure 29. Thiazole-pyrazoline hybrids with antitumor activity.
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Figure 27. Antitumor activity for pyrazoline-thiazolidinone based hybrids.
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Figure 30. Antitumor thiazolidinone/thiazole derivatives with pyrazoline moiety in 2 position. Figure 31. Antitumor benzofuran-pyrazoles with thiazolidinone/thiazole fragments.
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Figure 32. Antitumor activity of pyrazole-thiazolidinone-triazoles on lung cancer. Figure 33. 5-Pyrazoline-substituted pseudothiohydantoines as promising necroptosis inhibitors. Figure 34. Selective antitumor activity of pyrazole-rhodanine 4.25.
Figure 35. Bis-thiazolone with indazole fragment as potential inhibitor of CDC25V phosphatase. Figure 36. Antitumor activity of 4-thiazolidinones with pyrazolines in 5 position.
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Figure 37. Pyrazoline-thiazolidinone hybrids with antimicrobial activity. Figure 38. SAR analysis of antimicrobial pyrazole-thiazolidinone hybrids.
linker group.
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Figure 39. Antimicrobial and antifungal pyrazole-thiazolidinones/thiazoles, coupled by hydrazone
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Figure 40. Antimicrobial and antifungal activity for polyheterocyclic systems based on pyrazolethiazolidinones/thiazoles.
Figure 41. Antimicrobial activity of thiazolidines/thiazoles with 5-pyrazolone fragment. Figure 42. 3-Pyrazolinyl-4-thiazolidinones with antimicrobial activity. Figure 43. Pyrazole-pyrimidine-thiazolidinones as promising antimicrobial agents. Figure 44. Antimicrobial activity of 4-thiazolidinones with pyrazole in 5 position. Figure 45. Structure-antimicrobial activity relationship for pyrazole-rhodanine derivatives. Figure 46. Pyrazole/pyrazolines-thiazolidinone/thiazoles with antiviral activity.
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Figure 47. Antiviral and antitrypanosomal 5-pyrazoline substituted 4-thiazolidinones. Figure 48. SAR for trypanocidal 5-(pyrazolin-1-ylmethylene)-4-thiazolidinones. Figure 49. Pyrazoline-thiazolidinone hybrid with antiparasitic activity. Figure 50. Thiazolidinones and thiazoles with pyrazoline fragments as anti-inflammatory agents.
Figure 52. Pyrazole-thiazolidine hybrids as COX-2 inhibitors.
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Figure 51. Pyrazoline-thiazolidinone hybrids as COX-2 inhibitors.
Figure 53. ADAMTS-5 inhibitors among pyrazole-thiazolidinone hybrids.
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Figure 54. Pyrazole-thiazolidinones with anti-inflammatory activity.
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Highlights for the manuscript “Synthetic Approaches, Structure Activity Relationship and Biological Applications for Pharmacologically Attractive Pyrazole/Pyrazoline-ThiazolidineBased Hybrids”
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by Dmytro Havrylyuk, Olexandra Roman, Roman Lesyk
Synthesis and Chemistry of Pyrazole/Pyrazoline-Thiazolidine-Based Hybrids
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A diverse spectrum of Pyrazole/Pyrazoline-Thiazolidine-Based Hybrids biological
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activities has been presented.
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Structure activity relationship of Pyrazole/Pyrazoline-Thiazolidine-Based Hybrids for
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different activities has been discussed.