Pyrrole: An emerging scaffold for construction of valuable therapeutic agents

European Journal of Medicinal Chemistry 110 (2016) 13e31

Contents lists available at ScienceDirect

European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech

Review article

Pyrrole: An emerging scaffold for construction of valuable therapeutic agents Somnath S. Gholap Department of Chemistry, Padmashri Vikhe Patil College, Pravaranagar (Loni kd.), Rahata, Ahmednagar, 413713, Maharashtra, India

a r t i c l e i n f o

a b s t r a c t

Article history: Received 14 November 2014 Received in revised form 5 December 2015 Accepted 10 December 2015 Available online 13 December 2015

Pyrrole derivatives comprise a class of biologically active heterocyclic compounds which can serve as promising scaffolds for antimicrobial, antiviral, antimalarial, antitubercular, anti-inflammatory and enzyme inhibiting drugs. Due to their inimitable anticancer and anti-tubercular properties, researchers were inspired to develop novel pyrrole derivatives for the treatment of MDR pathogens. In the present review the main target is to focus on the development of pyrrole mimics, with emphasis based on their structure activity relationship (SAR). The present review is being obliging for the future development of pyrrole therapeutics. © 2015 Elsevier Masson SAS. All rights reserved.

Keywords: N-substituted pyrrole Fused pyrroles Natural pyrrole derivatives Therapeutic agents

Contents 1. 2.

3.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 Pyrrole derivatives as . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 2.1. Antimicrobials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 2.2. Anti-tubercular agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 2.3. Enzyme inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 2.3.1. CDK2 inhibitor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 2.4. Cytotoxic agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 2.5. Antiviral agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 2.6. Antimalarial . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 2.7. Anticancer agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 2.7.1. Antitumor agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 2.7.2. Anti-proliferative agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28 2.8. Miscellaneous . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28 2.8.1. Sodium and calcium channel blockers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28 2.8.2. Hepatoprotective agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 2.8.3. Trypanosomicidal agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 2.8.4. Hyperalgesia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 Conclusions and future prospects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30

E-mail address: [email protected]. http://dx.doi.org/10.1016/j.ejmech.2015.12.017 0223-5234/© 2015 Elsevier Masson SAS. All rights reserved.

14

S.S. Gholap / European Journal of Medicinal Chemistry 110 (2016) 13e31

1. Introduction Heterocyclic chemistry is being a significant division of organic chemistry. The molecules belonging this division have gain immense attention not only biological and industrial applicability but also developing human society. Heterocyclic compounds are pharmacologically active compounds accessed in laboratory as well as from natural sources. A wide practical applications of heterocycles can functioned as additives and modifiers in industries including cosmetics, polymers, solvents, antioxidants etc. Hence, synthesis of heterocyclic compounds has been a main objective of modern researchers. Among the new heterocyclic compounds, pyrrole has gain remarkable attention due to its biological potential as antimalarial and enzyme inhibiting properties. Pyrrole is a five membered heterocyclic aromatic compound with molecular formula C4H5N. It is a colorless volatile liquid that darkens readily upon exposure to air. Pyrrole is an essential component of more complex macromolecules including porphyrins of heme, chlorophyll, chlorins etc. It was first detected by F.F Runge in 1834 as a constituent of coal tar. In 1857, it was isolated from the

R2

R

NH NH N N

MeO

H N

MeO

Metacycloprodigiosin (15) R = Me Prodigiosin R1 (16) R = i-Pr

Steptorubin B (17) R2 = n-Bu

Fig. 2. Chemical structures of metacycloprodigiosin (15), prodigiosin R1(16) and streptorubin B (17).

pyrolysate of bone. Its name came from Greek pyrrols (fiery) from the reaction used to detect it-the red colour that it imparts to wood when moistened with hydrochloric acid.

NH2 NH2

Br X

HN

H N

N H

X

Hymenidin 1 X = Br 2X=H H2N

N

Br

Br

O Spongiacidin B (6)

Br

NH

N H

NH

NH COOH Longamide A (8)

Br

NH2 O

HN

Br Br

O

N

HO

NH

Br

N H Longamide B (9)

N H2N N HO HN N N H H2N Cl H

N

N H H N

NH

N

O

NH

Br

Br N H

H N

O

COOH

HN

NH NH2

Bromopyrrolohomoarginin (12)

O

Dibromopalu'amine (11)

Sceptrin (10)

H N

Br

H2N

NH2

Br

O

N

O

Bromoaldisin (7)

Br

O

Stevensine (5)

O

Br

NH

N H

Dispacamide B (3) R = H Dispacamide D (4) R = OH

HN Br

NH

Br

N O

O

O

N H

HN

R

H N

N H

O

N

NH2

Br

N

N H

O O

H N

Me

N COOH

N H

Manzacidin A (13)

Fig. 1. Potentially active pyrrole based natural products.

O

N+

O Agelongine (14)

COO-

S.S. Gholap / European Journal of Medicinal Chemistry 110 (2016) 13e31

R

N

N

Me N

O

R

N

N H

NH

Me

N

R

N

N

19

Ph N

R

R2

N

R1

N

R = 2-CH3, 4-OCH3

NH

Ph

N H

Ph N

NH2

22

R

R = H, 2-CH3, 4-OCH3 R

N

Ph

R 20

N N N N H

Ph

25

R1

R = H, 2-CH3, 4-OCH3

Ph

Ph

24

NHNH2 N

Ph N

N

N

27 R1 R = H, 4-OCH3

N R=H R1 = H, Ph R2 = H, 3,4-diclhoro

R

NH2

R = H, 4-OCH3

N N

NH2 N

NH2

26

O

Ph

NHCH3

Ph

21

R

R = 3-CH3, 4-OCH3

Ph

R

23

N N

N

NH2

Ph N CHOEt

N

R = H, 4-OCH3 R' = 4-OCH3Ph, 2-CH3Ph

OH

R = 3-CH3, 4-OCH3

CN

NHR'

Ph NH

Ph

R = H, 2-CH3, 3-CH3, 4-OCH3

Ph

N H

Me

NH2 30

S

Ph

NH2

N

NH2

Pyrrole derivatives are found in varieties of biological context as part of co-factors and natural products. Common naturally produced molecules containing pyrrole includes Vit.B12, bile pigments like bilirubin and biliverdin, porphyrins of heme, chlorophyll, chlorins, bacteriochlorins and porphyrinogens. One of the first syntheses of pyrrole containing molecule was that of haemin,

Fig. 3. Chemical structure of pyrrole based antimicrobial derivatives.

Ph

SH

N

N N

HS

N

Fig. 5. 1,3,4-oxathiazole and 1,2,4-triazole derivatives.

R = H, Cl, OH, NO2, OCH3

Ph

N

29

S 18

Me

Me

N H

NH

O

N

H2N

S

Me

NH2 S

N S

N

15

28

Fig. 4. Pyrroles and pyrrolo[2,3-d] pyrimidine derivatives.

16

S.S. Gholap / European Journal of Medicinal Chemistry 110 (2016) 13e31

their antimicrobial potential (Fig. 5). Gregory S. Basarab et al. [8] have investigated optimization of inhibitors toward identification of an antibacterial Clinical Candidate (AZD5099). Furthermore, incorporation of the methoxy substituent improved the target potency and incorporation of intramolecular H-bonding site improved the antibacterial activity (Scheme 1).

synthesized by E. Fischer in 1929 [1a,b,c]. Pyrrole was found to be core of huge family of biologically active natural products. Bromopyrrole alkaloids, including the oroidin analogues hymenidin (1, 2), dispacamide B (3) and dispacamide D (4), stevensine (5) and spongiacidin B (6), their derivatives lacking the imidazole ring bromoaldisin (7), longamide A (8) and longamide B (9), the dimeric oroidin derivatives sceptrin (10), dibromopalauamine (11), bromopyrrolohomoarginin (12), manzacidin A (13), and agelongine (14), obtained from marine sponges. Deniz Tasdemir et al. [2a] indicated that longamide B (9) and dibromopalau'amine (11) found to be promising trypanocidal, antileishmanial agents respectively. Dispacamide B (3) and spongiacidin B (6) emerge as antimalarial lead compounds (Fig. 1) [2b]. Natural products such as prodiginine and metacycloprodigiosin and prodigiosin R1 (15 and 16, Fig. 2) [3] had been found to be potent anti-malarial agents in mice. The activity of the prodiginines was dependent on the structural features of the molecules, including the ring size, ring substituents, and chirality. Streptorubin B (17, Fig. 2), shows less activity than 15.

2.2. Anti-tubercular agents Diarylpyrrole derivatives are known to be an effective drugs candidates against mycobacterial infection related to BM 212 (MIC ¼ 1 mg/ml). Among the synthesized derivatives 1-(4fluorophenyl)-2-ethyl-3-(thiomorpholin-4-yl)methyl-5-(4methylphenyl)-1H-pyrrole (35) is effective as BM 212 with MIC ¼ 1 mg/ml and protection index (PI) found to be better than reference compounds [9]. Other compounds were tested by Mariangela Biava et al. [9] and found to be active than parent 2methyl analogues (Fig. 6) [10]. In order to identify key structural fragments required for anti-TB activity, Kalyani D. Asgaonkar et al. [11] have studied QSAR (quantitative structure-activity relationship) model oxadiazoleligated pyrrole pharmacophore (42) and the binding ability with the enoyl-ACP (CoA) reductase. QSAR model will be useful for the development of new lead against multi drug resistant (MDR) mycobactariam (Fig. 7). Semicarbazide or thiosemicarbazide (43) possessing pyrrole core showed enhancement in their antimicrobial and antitubercular properties. Rane R. A. et al. [12] reported forty semicarbazide hybrids for antimicrobial screening and it has found that there is four-fold increased activity against E. coli than standard ciprofloxacin (MIC ¼ 0.39e1.56 mg/mL) (Fig. 8). Two well-known antibiotic as pyrrolnitrine (44) and banegazine (45), isolated from Zoobacteria Aristabacter necator, exhibit a synergic activity against Mycobacterium smegmatis MIC >0.5 mg/mL for 45, 0.3 mg/mL for 44, and 0.075 mg/mL for (44, 45) [13]. A similar
(46), a dichloropyrrol metabolite of strain Strepcelastramycin A tomyces exhibits a broad spectrum of antimycobacterial activity (MIC ¼ 0.05e3.1 mg/mL with respect to M. smegmatis, Mycobacterium aurum, Mycobacterium vaccae and Mycobacterium fortuitum) (Fig. 9) [14].

2. Pyrrole derivatives as 2.1. Antimicrobials Abdul Jamal Abdul Nasser et al. [4a,b] have been reported the synthesis of some tetra substituted pyrrole derivatives and screened for their biological potential against Escherichia coli and S. aureus. Pyrrole derivative 18 shows promising activity against E. coli (zone of inhibition 22 cm) using standard as ciprofloxacin (Fig. 3). A series of new pyrroles and pyrrolo[2,3-d] pyrimidine derivatives (19e28) were synthesized and screened in vitro antimicrobial potential against various Gram-positive, Gram-negative bacteria and fungi [5]. Some of the reported compounds showed potent antimicrobial activity and highly active antimycotic agents compared to fluconazole. In addition, Pyrrole has been utilized as a scaffold for the preparation of derivatives such as pyrrolo[2,3-d] pyrimidines and pyrrolotriazolopyrimidines. These compounds showed potent antimicrobial activity (Fig. 4) [6]. A. Jamal Abdul Nasser et al. [7] have been reported the synthesis of some pyrrole derivatives consisting 1,3,4-thiadiazole (29) and 1,2,4-triazole moieties. The synthesized compound checked for

Cl

Cl

O

O N H

S HN

N

OH

Cl

Cl

N H

N Lead compound 31

O

O S HN O

32

OH

N

N Key hydrophobic contact

Improved target potency

Cl

Intramolecular H-bond

Cl

O

O N H

S HN

OH H N

N N O

O

33 Improved antibacterial activity Lower in vivo clearance (rat, mouse, dog) Scheme 1. Synthesis of structurally diverse pyrrolamide topoisomerase II.

O

S.S. Gholap / European Journal of Medicinal Chemistry 110 (2016) 13e31

N

N

S

N

N

17

S

N

N

N

Cl Cl 34: BM 212 MIC = 1μg/ml PI = 4

N

F 36: MIC = 0.4μg/ml PI = 20

35: MIC = 1μg/ml PI = 32

S F N

N

S

N

S

N

N F

F

F

F 38: MIC = 1μg/ml PI = 32

37: MIC = 0.5μg/ml PI = 8

N

39: MIC = 0.5μg/ml PI = 16

S N

N

S

N

F

H3C F 40: MIC = 1μg/ml PI = 8

F 41: MIC = 25μg/ml PI = 256

Fig. 6. Chemical structures of 1,5-diarylpyrrole derivatives as analogue of BM 212(34).

2D QSAR sdsCHE Index essential for activity

3D QSAR Electopositive group increases anti-TB

O N H

2D QSAR Important for anti-TB 3DQSAR More hydrophobic group required for anti-TB activity

N N 42

3DQSAR Electronegative group is essential for maximal activity.

Fig. 7. Structure Activity Relationship (SAR) of pyrrole-ligated oxadiazole derivatives.

Lakshmi Reddy Pagadala et al. [15] has reported synthesis of a novel series of highly substituted pyrrole-N-acetyl derivatives (47) and evaluated for their anti-mycobacterial activity against M. smegmatis and Mycobacterium tuberculosis strain H37Rv. The tested

compounds showed potential toxicity against M. smegmatis and M. tuberculosis strain. In addition, cytotoxicity study of these compounds shows selectivity index: >16.83 against HEK-293T cell line (Fig. 10).

18

S.S. Gholap / European Journal of Medicinal Chemistry 110 (2016) 13e31

O2N

Pyrrole core R = H/CH3

H N

N H

O

43

X N H

N H

Ring B Ar = aryl/heteroaryl

Ar

X = O or S

Fig. 8. Antimicrobial semicarbazide derivatives.

Cl NO2 Cl

Cl

NH2

OH

NH Cl

COOH

N H

OH

N H

46

45: Banegazine

44: Pyrrolnitrine

Cl

O

Fig. 9. Structurally diverse antimicrobial agents.

O N O NHR

47

Fig. 10. Chemical structures of structurally diverse pyrrole derivatives.

selective inhibitors of class IIa HDACs. (Fig. 11) [16,17]. Frederick M. Pfeffer has reported the reassign structure of class IIa HDACs inhibitor (49) [18]. The research group of AstraZeneca has used a fragment-based lead generation approach for incorporation of known gyrase inhibitor fragments, such as pyrrole and they screened N-terminal ATP binding domain of E. coli GyrB by NMR screening using the 24 kDa. They have identified a pyrrolamide fragment (50) with MIC < lg/mL and Compound 51 with in vivo activity against selected Gram negative bacteria with 150-fold improvement of activity over Compound 50 (Fig. 12) [19].

O

O

N

NHOH N

O

F

NHOH O

F

48: MC 1568 (Class Selective)

49: Reassigned Structure Fig. 11. Chemical structures of HDAC inhibitors.

H N Cl

O

O2N

HN

H N

O S

N N 50

Cl

HN

COOH

N N

Cl 51

Fig. 12. Chemical structures of gyrase B/ParE inhibitors.

2.3. Enzyme inhibitors Pyrrole possessing hydroxamic acid functionality was exhibits enzyme inhibiting activities. MC1568 (48) is found to be one of the

N-Methylpyrrole (Py)-N-methylimidazole(Im) polyamides can recognize predetermined DNA sequences with high sequence specificity. Yong-Woon Han et al. [20] has synthesized various hairpin Py-Im polyamide derivatives like 52, which recognize 50-

S.S. Gholap / European Journal of Medicinal Chemistry 110 (2016) 13e31

GCGC-30 and studied their binding behavior with surface plasmon resonance assay (Fig. 13). In order to find out selective enzyme inhibitors, Andrej Perdih et al. [21] have been reported four members of the bacterial Mur ligase family viz. MurC, MurD, MurE and MurF were involved in the intracellular steps of peptidoglycan biosynthesis, and catalyzes the synthesis of the peptide moiety of the Park's nucleotide (Scheme 2). Using a fragment-based in silico screening approach, Hongtao Zhao et al. [22] has identified two small molecules that bind to the first bromodomain of BRD4 (55) with low-micromolar affinity and favorable ligand efficiency (0.37 kcal/mol per non-hydrogen atom), selectively over other families of bromodomains. It is important to note that the hit rate of the fragment-based in silico approach is about 10% as only 24 putative inhibitors (Fig. 14). Aldose reductase inhibitors (ARIs) are responsible for long-term diabetic complications and inflammatory pathologies. The poor membrane permeation of ARIs, derivatives of N-phenylpyrrole, bearing groups with putative pKa ¼ 7.4, were synthesized by Maria Chatzopoulou et al. [23] and evaluated for aldose reductase inhibitory activity. It has been observed that 2-fluorophenol group was the most promising moiety. The most active compound (57), reported as a submicromolar inhibitor (IC50 ¼ 0.443 mM) and also selective against the homologous enzyme aldehyde reductase (Scheme 3).

Fig. 13. Structure of Py-lm polyamide.

O

HOOC

HOOC NH

N O

19

N

S N

S

HOOC

O

HOOC

Cl 54

53

MurC = 40 μM MurD = 60 μM MurE = 93 μM MurF = 89 μM

MurD = 689 μM MurE = 39 μM Dual Mur ligase inhibitor

N

NH

Multiple Mur ligase inhibitor

Scheme 2. Chemical structures of ligase inhibitors.

Francesco Casuscelli et al. [24] has reported a novel series of PIM inhibitors by natural product-inspired library generation starting from Longamide B (58) and their biological screening. The pyrrolo [1,2-a]pyrazinones (59, 60) initial hits are inhibitors of PIM isoforms with IC50 values in the low micromolar range has been reported by authors. The synthesis, structure-activity relationship was studied and the cellular activities including inhibition of cell growth and modulation of downstream targets are also described (Scheme 4). Recently, the structure-activity relationship (SAR) study of chemotype (61) identified as inhibitors of the human NADþ-

N O Ligand efficiency 0.37 55 Fig. 14. Chemical structure of BRD4 inhibitor.

O

O

O F

N

F

N

O

mildly-acidic moiety

N

F OH 56

F OH 57

Scheme 3. Synthesis of N-pyrrole derivatives as aldose reductase inhibitor.

20

S.S. Gholap / European Journal of Medicinal Chemistry 110 (2016) 13e31

O

O

NH N

Br

N

COOH

Br

Br

S

Longamide B

O

NH O

O

N

HN

HN

Br

PIM1 IC50 = 1.441 μM

58

NH

Cl

59

60

N

N

PIM1 IC50 = 3 nM PIM2 IC50 = 73 nM PIM3 IC50 = 12 nM

Scheme 4. Structurally modified Longamide B.

The carboxylic acid derivative 63 was identified as a potent and promising 5-HT4 receptor antagonist with moderate affinity for the AT1 receptor (Scheme 5). A series of pyrrole based 6-acylureido derivatives were synthesized as potential dual Aurora B/FLT3 inhibitors by replacing the 6-arylureido moiety in 6-arylureidoindolin-2-one-based multikinase inhibitors (Scheme 6) [27]. Hsiao-Chun Wang et al. [28] has reported some pyrrole derivatives with bioisosteric replacement of an acylureido moiety

N

N N N

HPGD(IC50) = 34 nM 61 Fig. 15. Chemical structure of chemotype identied as HPGD.

N O

N O

NH O

N

NH

CO2H

O

N

63

62 Scheme 5. Synthesis of AT1 receptor ligands.

N

O N H MeO

N H O

O N H

N H

64 Multi-RTK inhbitor

Linker modification

N H

HN O MeO

N H O

O N H

N H

65 Dual Aurora B/FLT3 Inhibitor

Scheme 6. Synthesis of 6-acylureido derivatives.

dependent 15-hydroxyprostaglandin dehydrogenase (HPGD, 15PGDH) has been reported by Damien Y. Duveau et al. [25] Lead from both series displayed potent inhibition (IC50 < 50 nM), demonstrate excellent selectivity towards HPGD and potently induce PGE2 production in A549 lung cancer and LNCaP prostate cancer cells (Fig. 15). Fused pyrrole based Serotonin (5-hydroxytryptamine, 5-HT) have been found to be an important signaling molecule in the central nervous system (CNS). Bjarne Brudeli et al. [26] reported a new series of peripherally-acting 5-HT4 receptor antagonists combining the acidic biphenyl group from the class of angiotensin II receptor blockers (ARBs) with the SB207266 (piboserod) scaffold.

attached to indolin-2-one scaffold with a malonamido (66) or a 2/4pyridinoylamido (67) moiety produces a selectively potent AuroraB inhibitor (Scheme 7). Pyrrole ketones (68) has been reported as Lactate dehydrogenase A (LDH-A). It is noteworthy that the synthesized compounds can decrease the expression of hypoxia inducible factor (HIF-1a) in HepG-2 cells (Fig. 16) [29]. R. Silvestri et al. [30] has described the synthesis of some NBenzyl- and N-propargyl-1H-pyrrole-2-carboxyamide derivatives (69e72) and evaluated for their monoamine oxidase types A and B inhibitory potential. In their study the have found that 2-(NMethyl-N-propargylaminomethyl)-1H-pyrrole (70) was the most

S.S. Gholap / European Journal of Medicinal Chemistry 110 (2016) 13e31

O

O N H

Bioisosteric modification

N H O

R

N H

N H

O

N H O

O N H

N H

N H

21

Multi-Kinase inhbitor Multi-Kinase inhibitor conformational restrictions

O R

N H O

O

N

N H

N H

O R

N H

N H N H

66

N H O

O

Selective aurora B inhibitors

67

Scheme 7. Synthesis of pyrrole derivatives as potential aurora B inhibitors.

N

O N H

N H

O

11 H3 CO

68

LDH Inhibitor Decreasing Expression of HIF Fig. 16. Chemical structure of Lactate dehydrogenase A (LDH-A) inhibitor.

R5 R2 N N R1

N R1

R3

X

X

X = O; R1-R5 = H, Me

69

R2 N N H

R2 N

R4

N

70

H N

O

N H

O 71

O 72

Fig. 17. N-Benzyl- and N-propargyl-1H-pyrrole-2-carboxyamide derivatives as monoamine oxidase types A and B inhibitors.

O

H N

O

N H 73 Fig. 18. Pyrrolocarbazole as PARP-1 inhibitor.

N H O N H 5-[11C]methoxy-sunitinb 74

Fig. 19. Structure of Sunitinib analogues and studied their tyrosine kinase inhibitor of VEGFR-2.

potent MAO-A inhibitor (0.0054 mM) with absence of selectivity (Fig. 17). M. Tao et al. [31] has reported the synthesis of pyrrolocarbazoles and studied their potential as PARP-1 inhibitors. Pyrrolocarbazole (73) was identified as a potent PARP-1 inhibitor (IC50 ¼ 36 nM) (Fig. 18). J. Caballero et al. [32] were reported the Synthesis, in silico, in vitro, and in vivo investigation of sunitinib analogues and studied their tyrosine kinase inhibitor of VEGFR-2. In the present report the synthesis of 5-methoxy-sunitinib (74) and its 11C-radiolabeled analogue [11C]-5 (Fig. 19) has been stated. A binding constant for compound-5 was Kd ¼ 20 nM. A. Wiegard et al. [33] has described the synthesis of pyrrole alkanoic acid derivatives as nuisance inhibitors of microsomal prostaglandin E2 synthase-1. They have identified 3-(4dodecanoyl-1,3,5-trimethylpyrrol-2-yl)propionic acid (75) as submicromolar inhibitor of mPGES-1 and some of the synthesized compounds were investigated for inhibition of human recombinant mPGES-1 also in presence of the detergent such as Triton X-100 (Fig. 20). F. Piscitelli et al. [34] has been utilized 1-aryl-5-(1H-pyrrol-1yl)-1H-pyrazole-3-carboxamide analogues (7678) as an effective scaffold for the design of cannabinoid (CB) receptor ligands (Fig. 21). J. Sasaki et al. [35] has been studied the synthesis and in vitro evaluation of radioiodinated indolequinones targeting NAD(P)H:

22

S.S. Gholap / European Journal of Medicinal Chemistry 110 (2016) 13e31

O

Inhibition of human recombinant mPGES-1 - in absence of Triton X-100: IC50 = 0.14 μM -in presence of Triton X-100: not active at 10 μM

C11H23 H3C

COOH

N CH3

75

Fig. 20. Pyrrole alkanoic acid derivatives as nuisance inhibitors of microsomal prostaglandin E2 synthase-1.

Cl O

Cl

O

HN

O

HN N

N

N

N

HN

Cl

N

N

N

Cl

Cl

Cl

Cl 77

76

N

N

Cl 78

Fig. 21. Structures of 1-aryl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamide analogues as cannabinoid (CB) receptor ligands.

H N N

125

I O R1

O

S

O

N CH3 79

CH3

O

O

NH2

NH2 CF3

N

N

H2N

N

H2N 80: JAK2 IC50 = 3.2 μM

N H Cl

81: JAK2 IC50 = 0.008 μM

Fig. 23. Pyrrole-3-carboxamides analogues as JAK2 inhibitors.

R

O

R O

Fig. 25. 3-Amino-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole derivatives as selective CDK inhibitors.

[125I]

Fig. 22. Radioiodinated indolequinones targeting NAD(P)H: Quinone oxidoreductase 1.

N

N 83

H3CO

N H

N H

Quinone oxidoreductase (79) for internal radiation therapy. The NQO1-targeted radioiodinated compound [125I] could be used as a novel internal radiation agent for the treatment of cancer (Fig. 22). M. G. Brasca et al. [36] have reported the synthesis of pyrrole-3carboxamides derivatives as novel class of JAK2 inhibitors (80, 81). The study led to the identification of the potent and orally bioavailable JAK2 inhibitor as Compound 81 (IC50 ¼ 0.008 mM) (Fig. 23). 2.3.1. CDK2 inhibitor K. C. Luk et al. [37] has described the synthesis of a pyrrole based oxindole derivatives as potential CDK2 inhibitor. The 4-alkynylsubstituted compounds (82) remarkable inhibitory effect against CDK2 (Fig. 24). P. Pevarello et al. [38] has been described the synthesis of 3Amino-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole derivatives (83) accomplished using a solution-phase protocol and their potential as selective CDK inhibitors (Fig. 25). 2.4. Cytotoxic agents

N H O

F N H 82

Fig. 24. Pyrrole based oxindoles as CDK2 inhibitor.

Halitulin is a natural product isolated from the marine sponge Haliclona tulearensis [39,40]. It has remarkable biological potential such as cytotoxicity against several tumor cell lines at concentrations of 12e25 ng mL1. Structural modification in Compound 84, with two nitrocatechol moieties as substituents of the pyrrole ring and a 3-(azatricyclodecan-1yl)-propyl group on the Compound 85, nitrogen showed highest cytotoxic activity among the series of

S.S. Gholap / European Journal of Medicinal Chemistry 110 (2016) 13e31

OH HO

HO

HO

OH

OH HO

OH

O2N

N

N

23

NO2

N

N

N

N

85

84 Fig. 26. Structure of Halitulin and analogue.

HO MeO

HO

O

N

HO O

N

MeO HO

MeO

OH

MeO

N

HO

O

OH

MeO

O O

MeO

MeO

N

MeO

O

O

HO

MeO

Mono-Mannich derivative

N

GI50(HT-29)< 2.64± 0.38μM 87

GI50(HT-29)< 6.41± 1.97μM 88

OH

N

86: Lamellarin D HO

GI50(HT-29)< 4.47± 1.69μM

O

N

MeO

O MeO N

HO

OH

MeO 89

Bis-Mannich derivative GI50(HT-29)< 2.83± 0.39μM Scheme 8. Synthesis of structurally modified Mannich bases of Lamellarin D analogue.

HOOC

O

Boc N

OH H N

O PBD Building Block (90)

R

O O

N

H N

MeO O

PBD Conjugate: R = Pyrroline (91), Piperidine (92), Indoline (93) and Isoindoline (94)

Fig. 27. Pyrrolo[2,1-c][1,4]benzodiazepine analogues with highest DNA-binding affinity.

compounds synthesized (Fig. 26) [41]. Li Shen et al. [42] has synthesized a series of Mannich derivatives of lamellarin D (86) from vanillin and isovanilin and evaluated for their in vitro anti-cancer and Topo-I inhibitory activities. The results obtained showed that most target compounds

(87e89) exhibited Topo I inhibitory activities in equivalent level with that of lamellarin D (Scheme 8). Luke A. Masterson et al. [43] has been reported the synthesis of a series of pyrrolo[2,1-c][1,4]benzodiazepine (PBD) analogues 91e94 from 90. The synthesized Compound 90 showed most cytotoxcity

24

S.S. Gholap / European Journal of Medicinal Chemistry 110 (2016) 13e31

N

O

R NH

O

O

O

MeO

O

MeO

N

N

O

Cl

O

Cl

96

95: R = H, TS

Fig. 28. Indomethacinr derivatives as cytotoxic agents.

COOH

O O

N

N H

N

Me

HO

O

R1

98: R1 = Me; R2 = COMe; R3 = Ph 99: R1 = R2 = Me; R3 = COMe 100: R1 = COMe; R2 = H; R3 = NO2 101: R1 = H; R2 = R3 = - COOEt

Fig. 30. Chemical structure of 1-b-D-ribofuranosylpyrroles as anti-HIV1.

COOH HO

HO N

O

N S

102: IC50 37.4 μM (gp41-6HB) EC50 0.7 μM 9(cells)

105: NB-64 ClogP: 3.15

Fig. 31. Chemical structures of N-pyrrole derivatives as anti-HIV1.

OH OH

COOH

N

Me

104: NB-2 ClogP: 4.28

R2 N

N

97

Fig. 29. Chemical structure of thieno[3,2-b]pyrrole as potent antiviral.

R3

HOOC

O

F S

Cl

HO

N

R

S 103: IC50 1.8 - 2.6 μM (gp41-6HB) EC50 0.3 - 1.5 μM 9(cells)

Scheme 9. Synthesis of pyrrole derivatives as anti-HIV1gp41 agents.

and highest DNA-binding affinity (Fig. 27). J. S. Moreno et al. [44] has reported the synthesis of the novel pyrrole based indomethacin ester derivatives (95, 96) and studied their cytotoxic effects in primary calvarial osteoblasts (Fig. 28).

validated a thieno[3,2-b]pyrrole compound (97) with a half maximal inhibitory concentration of <10 mol/L, a selectivity index >20, and potent activity against live virus in cultured neuronal cells. They studied structure-activity relationship of twenty related compounds in order to enhance activity profiles of these compounds (Fig. 29). A. M. Almerico et al. [46] have been studied the synthesis of new 1-b-D-ribofuranosylpyrroles of type (98e101) and antiviral activity targeting HIV-1 (Fig. 30). A series of pyrrole derivatives(Z)-3-(5-(3-benzyl-4-oxo-2thioxothiazolidinylidene)methyl)-N-(3-carboxy-4-hydroxy) phenyl-2,5-dimethylpyrroles (102, 103) by scaffold elongation strategy consisting a linear multi-aromatic-ring skeleton were designed as reported by Xiao-Yang He et al. [47] and evaluated against HIV-1 gp41 and cellular response. It has been found that among prepared compounds, compounds (103) with a one-carbon linker (n ¼ 1) between the rhodanine and phenyl rings showed promising inhibitory potency with IC50 values of 1.8e2.6 mM and EC50 values of 0.3e1.5 mM against gp41. In addition these compounds were effective against both T20-sensitive and resistant strains (Scheme 9). N-substituted pyrrole derivatives having ability to interfere with the gp41 six-helix bundle formation and block virus fusion. Shibo Jiang et al. [48] were identified two N-substituted pyrroles,

O

R3

2.5. Antiviral agents It is noteworthy that neurotropic alpha viruses such as western, eastern and Venezuelan equine encephalitis viruses cause serious central nervous system infections in humans and are regarded as potential bioterrorism agents. Now a day, there is absence of broadline vaccines or licensed therapies for treatment of these virulent pathogens. David J. Miller et al. [45] were identified and

N R1

HN R2

106: Prodiginines Fig. 32. Chemical structure of Prodiginine derivatives.

S.S. Gholap / European Journal of Medicinal Chemistry 110 (2016) 13e31

NH N N

R

HN

HN

NH2 107: Aplidiopsamine A

O

N

N

N

N

N

NH

NH

NH N

25

108: Marinoquinoline A (R = H) 112: Marinoquinoline E 109: Marinoquinoline B (R = -i-Pr) 110: Marinoquinoline C (R = Ph) 111: Marinoquinoline D (R = 4-HO-Ph)

113: Marinoquinoline F

Fig. 33. Chemical structures of antimalarial natural pyrrole derivatives.

O O O

2.6. Antimalarial

H

O

H

In vitro, IC50 = 3.8 nM K1 Plasmodium falciparium in vivo ED50 po = 2 mg/kg; ED90 po = 5.2 mg/kg-Plasmodium berghei

N N

N

114 Fig. 34. C-10 pyrrole Mannich base derivatives of Artemisinin.

designated NB-2 and NB-64, that inhibited NB-2 and NB-64 (104, 105) that inhibited HIV-1 replication at a low micromolar range. The absence of the COOH group in NB-2 and NB-64 resulted in a loss of anti-HIV-1 activity, suggesting that this acid group plays an important role in mediating the antiviral activity and SAR study. Docking analysis study of these compounds showed that they fit inside the hydrophobic pocket and that their COOH group interacts with a positively charged residue (K574) around the pocket to form a salt bridge (Fig. 31).

In order to identify the potent lead and to improve the antimalarial activity of pyrrole derivatives, Vesna Rastija et al. [49] has carried out docking study of forty-nine synthetic prodiginines (106) possessing moderate to high activities against multi drug resistant (MDR) strain of Plasmodium falciparum. The docking analysis results revealed that certain groups/atoms like eF, benzylic eCH2e and eOCH3 play crucial role in deciding the antimalarial activity of prodiginines (Fig. 32). There are some potential drug isolated from natural product including Morphine (from the opium poppy Papaver somniferum), Penicilin G (Penicillium fungi) and polyaromatic alkaloid such as Aplidiopsamine A (107) (Australian ascidian Aplidiopsis confluata) possessing the tricyclic aromatic substructure 3H-pyrrolo[2,3-c] quinoline core [50a,b]. The other natural product such as Marinoquinoline A (108) isolated from marine bacterium Rapidithrix thailandica possessing 3H-pyrrolo-[2,3-c]quinoline core and Marinoquinoline BeF(109e113) (Fig. 33) [51]. Paul M. O'Neill et al. [52] had studied the antimalarial assessment of C-10 pyrrole Mannich base derivatives of Artemisinin (114). They have studied in vitro analysis of these derivatives against both chloroquine sensitive and resistant strains. The presence of morpholine and N-methylpiperazine Mannich side chains exhibited best activity profiles (Fig. 34).

H N

H N

Br

O N H 116

O N

N H

N H

Br

NH2

H N

Br

O N H

Br

115: Oroidin

117 H N

Br

O N H

Br 118 Enhanced cytotoxicity GI50 < 5 μM Scheme 10. Synthesis of oroidin analogues as potential anticancer agents.

26

S.S. Gholap / European Journal of Medicinal Chemistry 110 (2016) 13e31

N N

O

H N

N H

O

N H O

F

N H O

F

N H

N H

N H 121

120

119: Sunitinib

N

H N

O

N H O

F

N

VEGFR-2 3.8nM PDGFR-B 19nM VEGFR-1 1.1μM hERG 18.8μM HT-29 Body Weight Change 6.2%

VEGFR-2 9nM PDGFR-B 8nM VEGFR-1 2nM hERG 0.5μM HT-29 Body Weight Change -24.1%

Fig. 35. Synthesis of structural analogues of sunitinib as anticancer agents.

2.7. Anticancer agents

OCH3 O OCH3 OCH3

N

122: ARAP NH2

TPI 1.5 μM

Fig. 36. Anticancer 3-aroyl-1-arylpyrrole.

OH S

OH S

N

OH

N

OH

124 HO Enhanced activity against Triple-Negative Breast Cancer

123

Scheme 11. Synthesis of 6,7-bis(hydroxymethyl)-1H,3H-pyrrolo[1,2-c]thiazole derivatives as anticancer agents.

O

O

O NH

HN H2N

N

HN

N H

N 125

Oroidin (115), (E)-N-[3-(2-amino-1H-imidazol-4-yl)allyl]-4,5dibromo-1H-pyrrole-2-carboxamide is a pyrrole alkaloid isolated from the marine sponge Agelas oroides. It showed poor cytotoxcity in a panel of twelve cancer cell lines (50% growth inhibition concentration GI50 ¼ 42 mM in MCF-7 cells and 24 mM in A2780 cells and >50 mM in all other cell lines tested). Lauren Dyson et al. [53] has been reported the enhancement of cytotoxicity by structural modification in oroidin. Among synthesized compounds, N(biphenyl-4-ylmethyl)-1H-pyrrole-2-carboxamide (116), N-benzyl4,5-dibromo-1H-pyrrole-2-carboxamide (117) and N-(biphenyl-4ylmethyl)-4,5-dibromo-1H-pyrrole-2-carboxamide (118) was found to be potent inhibitors of cell growth cell lines (Scheme 10). A series of pyrrole analogues were synthesized, and evaluated in vivo activity or toxicity relationship of indolin-2-one (119) structural analogues showed anticancer activity (120,121). Kinase assay Compound 119 was investigated against VEGFR-2, VEGFR-3, FLT3, Ret and PDGFR-b kinases and was identified as a drug candidate for the treatment of cancer (Fig. 35) [54]. Synthesis of 3-aroyl-1-arylpyrrole (ARAP) (122) derivatives as potential anticancer agents (TPI 1.5 mM) having different substituents at the N-phenyl ring have been reported by Romano Silvestri et al. (Fig. 36) [55]. Fused pyrrole derivatives showed remarkable anticancer activity as stated by Kathleen Santosa et al. [56]. In this report they have studied on synthesis of 6,7-bis(hydroxymethyl)-1H,3H-pyrrolo[1,2c]thiazole derivatives 123, 124 as anticancer agents against triplenegative breast cancer. These compounds were assayed for their in vitro cytotoxicity on several human breast cancer cell lines (MCF7, HCC1954 and HCC1806 cell lines). The presence of hydroxyl substituent at 124 enhanced the anticancer activity (Scheme 11).

Fig. 37. Antitumor pyrrolo[2,3-d]pyrimidines derivatives.

Z

X H

NH2

CN

N

N CN

N

R N 126 X = O or NH R = aryl or hetaryl

N

Y

N 127

N

N N

N 128 Y = amino, imino, oxo Z = CH3, thio, alkylthio

Fig. 38. Pyrrolylpyridine derivatives as antitumor agents.

N N

129 R = H or CH3

R

S.S. Gholap / European Journal of Medicinal Chemistry 110 (2016) 13e31

S

R3

OR2

N

N

R1

R1

O N

N N 131

Fig. 40. Pyrrole based bis-chalcones as cytotoxic agents.

OH

OH OH S

N

S

S

N

132: IC50 = 2.4μM

133: IC50 = 29.9μM

N

S OH

135: IC50 = 22.6 μM

OH S

N

Ph

OH

134: IC50 = 1.0μM

OH

OH S

N

Ph

Ph

Ph

N

OH

OH

Ph

Ph

137: IC50 = 0.5μM

136: IC50 = 52.1μM

Fig. 41. 6,7-bis(hydroxymethyl)-1H,3H-pyrrolo[1,2-c]thiazoles as anticancer agents.

2.7.1. Antitumor agents Y. Liu et al. [57] has been described the Synthesis and antitumor activity of a novel series of 6-substituted pyrrolo[2,3-d]pyrimidines (125) as potential non classical antifolates targeting both thymidylate and purine nucleotide biosynthesis (Fig. 37). S. A. F. Rostom and A. A. Bekhit had described the synthesis of di, tri- and tetracyclic pyrrolylpyridine derivatives (126e129) using both the conventional heating and MW irradiation techniques

O N

R1

N H

H N

N R5

N . HCl 140: R1 = H, Me, NH2 R2 = H, Me R3 = H, OMe R4 = H, OMe R5 = H, Me

H N

N . HCl 141

Fig. 43. Pyrrolo[3,2-d]pyrimidine derivatives as antitumor agents.

O

N

N

R2

N

Fig. 39. l,2,3-bis(hydroxymethyl)benzo[d]pyrrolo[2,1-b]thiazoles and their bis(alkylcarbamate) derivatives as antitumor agents.

N

H3CO

R4

OR2

130: R1 = Alkyl or substituted phenyl R2 = H, CONHEt, or CONH-i-Pr

27

O

R1 = Ph, Y = CH2 R1 = Me, Y = CH2 R1 = Me, Y = CH2 CH2

S

Y N

Y

N

studied their antitumor potential. If R ¼ 3,4-di-OCH3-C6H3 exhibited prominent antitumor activity (Fig. 38) [58]. R. Chaniyara et al. [59] has been developed a series of l,2,3bis(hydroxymethyl)benzo[d]pyrrolo[2,1-b]thiazoles and their bis(alkylcarbamate) derivatives (130). The anti-proliferative activity of these agents against human leukemia and various solid tumor cell growth in vitro has been studied. The SAR studies revealed that the bis(alkylcarbamates) derivatives are usually more cytotoxic than the corresponding bis(hydroxymethyl) congeners in inhibiting human lymphoblastic leukemia CCRF-CEM and various human solid tumor cell growth in culture (Fig. 39). J. D. Solano et al. [60] has been reported pyrrole based bischalcones (131) and studied their cytotoxicity with massive vacuolation in HeLa cervical cancer cell line (Fig. 40). M. I. L. Soares et al. [61] described the synthesis and biological evaluation of 6,7-bis(hydroxymethyl)-1H,3H-pyrrolo[1,2-c]thiazoles (132e137) as anticancer agents against MCF7 breast cancer cell lines (IC50 ¼ 1.0 mM). The compounds screened by M. I. L. Soares et al. showed (3S)-6,7-Bis(hydroxymethyl)-5-methyl-3-phenyl1H,3H-pyrrolo[1,2-c]thiazole proved to be the most potent against cancer cell line (IC50 ¼ 0.5 mM) (Fig. 41). A. Lauria et al. [62] has been reported synthesis and antitumor evaluation of new annelated pyrrolo-pyrimidine derivatives (138, 139). The study involves the application of the chemometric protocol VLAK to predict improvement of the biological activity of pyrrolo-pyrimidine derivatives as anticancer agents (Fig. 42). A. Gangjeea et al. [63] designed, synthesized and studied antitumor potential of some pyrrolo[3,2-d]pyrimidine derivatives (140,141). These compounds inhibit proliferation of MDA-MB-435 tumor cells and displace colchicine binding to tubulin (Fig. 43). M. I. El-Gamal and C. H. Oh [64] reported the design and synthesis of a series of diarylureas and diarylamides possessing pyrrolo [2,3-d]pyrimidine scaffold (142,143). The in vitro antiproliferative

S

Ph

138

139

IC50 = 26.7 μM IC50 = 23.2 μM IC50 = 41.2 μM

N R2

R2 = H, Y = NMe R2 = Me, Y = CH2 R2 = H, Y = CH2 CH2

Fig. 42. Pyrrolo-pyrimidine derivatives as antitumor reagents.

Ph IC50 = 36 μM IC50 = 10 μM IC50 = 10.5 μM

28

S.S. Gholap / European Journal of Medicinal Chemistry 110 (2016) 13e31

H N O

H N

N N

H N

H N

Ar

O

N

O

142

H N

N N

Ar O

N

143

Fig. 44. Diarylureas and diarylamides as antiproliferative agents.

R5

X

R4

Y

R

R1

N +

H2N

NH

X

R4

Y

R

HN

CH3COO-

NH

R

R1

N

R2

W

R5

W

R2

R5

N R2 R3

145

144: X = N, Y = CH, W = C-R3 X = CH, Y = N, W = C-R3 X = Y = CH, W = N

R4

R1

X

R6 NH

R7

146: X = NH, NH2+CH3COO-

Fig. 45. Fused pyrido[20 ,30 :3,4]pyrrolo[1,2-a]quinoxalines as anti-proliferative agents.

O

O NH2

N

N

Cl

Cl

R2

Cl

N

N

N H

NH2

N

N

N NH2

147

148

151

Fig. 46. Pyrrole carboxamide derivatives as anti-myeloproliferative agents.

N R1

Fig. 47. Chemical structure of tetrahydropyrrolo[3,4-c]pyrazoles.

activities of some of these compounds were studied against NCI60 cell line panel. Most of the compounds showed strong and broad-spectrum antiproliferative activities as compared to Sorafenib and Imatinib as reference compounds (Fig. 44).

2.7.2. Anti-proliferative agents B. Parrino et al. [65,66] described the synthesis of structurally diverse fused pyrroles such as pyrido[20 ,30 :3,4]pyrrolo[1,2-a]quinoxalines (144), pyrido[30 ,20 :3,4]pyrrolo[1,2-a]quinoxalines (145) and pyrido[20 ,30 :5,6]pyrazino[2,1-a]isoindoles (146) (Fig. 45). The biological evaluation study indicated the anti-proliferative effect of these class of compounds (pGI50 ¼ 7.09e7.27). M. G. Brasca et al. [67] has been described the synthesis of novel pyrrole carboxamide derivatives (147, 148) as JAK2 inhibitors and can be used against myeloproliferative disorders. Compound 147, displaying activity against JAK2, Compound 148 potent and orally bioavailable JAK2 inhibitor (NMS-P830) (Fig. 46).

H N

N

O OR2

Fig. 48. Chemical structures of natural hepatoprotective pyrrole derivatives.

2.8. Miscellaneous 2.8.1. Sodium and calcium channel blockers Shu-Wei Yang et al. [68] have been synthesized a series of pyrrolo-benzo-1,4-diazine analogues (149, 150) and potent Nav1.7 inhibitory activity and moderate selectivity over Nav1.5. Compound 150 displayed anti-nociceptive efficacy in the rat CFA pain model at 100 mpk oral dosing (Scheme 12).

O

R2,R3

N

149

N

L

R1

O

H N

N O

N L: linker

152: R1=H; R2= H 153: R1=CH3; R2= H 154: R1=CH3; R2= CH3 155: R1=H; R2= CH3

CHO

R1O

150

Scheme 12. Synthesis of pyrrolo-benzo-1,4-diazine analogous.

N

S.S. Gholap / European Journal of Medicinal Chemistry 110 (2016) 13e31

O

29

O Me

EtOOC N Et

OMe EtOOC N Et

O O 156

IC50 = 20nM (On epimastigote culture)

O O 157 20 nM

Fig. 49. Chemical structures of indole-4,9-dione as potential trypanosomicidal agents.

HN O H3CO2S

(CH2)nONO2 COOH

N R 159

HN (CH2)nONO2

H2N

HN (CH2)nONO2

O

O

N

H3CO2S

H3CO2S

N

R

R

158

160

Scheme 13. Synthesis of structurally modified pyrrole derivatives as a hyperalgesia agents.

ONO2

O

R

O

N

NH2 MeO2S

Linker

161

Fig. 50. Nitric oxide releasing pyrrole derivatives as anti-inflammatory agents.

Michael P. Winters et al. [69] had reported a novel series of substituted tetrahydropyrrolo[3,4-c]pyrazoles (151) and investigated as N-type calcium channel (Cav2.2 channels), a chronic pain target (Fig. 47). 2.8.2. Hepatoprotective agents Jinwoong Kim et al. [70] reported the isolation of hepatoprotective compounds from Lycium chinense fruits, three new pyrrole derivatives (152e154). These compounds and a related synthetic methylated compound (155) were evaluated for their biological activity and SAR (Fig. 48). 2.8.3. Trypanosomicidal agents Ricardo A. Tapia et al. [71] have synthesized indole-4,9-dione and their phenoxy derivatives (156, 157) (Fig. 28) for in vitro evaluation against the epimastigote form of Trypanosoma cruzi, Y strain. They have identified phenoxyindole-4,9-dione 156 as excellent inhibitor (IC50 ¼ 20 nM, and high selectivity index, SI ¼ 625)

(Fig. 49). 2.8.4. Hyperalgesia Mariangela Biava et al. [72] have been reported the synthesis, physicochemical and pharmacological investigation of the pyrrole derivatives (158e160) as a novel pharmacodynamic hybrids for selective inhibition of cyclooxygenase-2 (COX-2) isoform and nitric oxide releasing properties. They have found that the replacement of the ester moiety with the amide group exhibited excellent pharmacological properties (Scheme 13). 2.8.4.1. Anti-inflammatory. M. Biava et al. [73] had improved the solubility of pyrrole derivatives (161) as a new class of antiinflammatory pharmacodynamic hybrids that release nitric oxide and inhibit cycloxygenase-2 isoenzyme. These derivatives showed enhanced nitric oxide releasing properties due to the presence of an ionisable moiety (Fig. 50). 3. Conclusions and future prospects This review described the synthetic potential of various pyrrole derivatives that have been published in the literature. Many therapeutic agents starting from pyrrole scaffold have been obtained was highlighted in this review. Essentially, numerous diverse Nsubstituted, C-substituted pyrrole derivatives have been found to be most potent as antimicrobial, anticancer, antiviral, antimalarial, anti-tubercular, cytotoxic etc. agents. Most of these lead are accessible from easily or commercially available low-cost starting

30

S.S. Gholap / European Journal of Medicinal Chemistry 110 (2016) 13e31

materials and processes. The present review has also demonstrated the synthesis, structural modifications of various pyrrole drugs. The synthesis of the pyrrole based heterocycles are illustrated in this review will be useful for further development of medicinal chemistry and applications of new pyrrole based promising building block. Acknowledgement Authors are thankful to UGC, New Delhi for financial assistance, Principal, P.V.P College, Pravaranagar for providing necessary facilities and Dr. C. H. Gill, Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad for constant encouragement. References [1] a) G. Marc, Chemistry of Naphthalene and the Aromatic Heterocycles. Organic Chemistry, fourth ed., Oxford University Press, , New York, 2000, ISBN 0-19511999-1, pp. 1135e1136; b) C. Michael, A.L. Lehniger, D.R. Nelson, Lehniger Principles of Biochemistry, Worth Publisher, New York, 2000, ISBN 1-57259-153-6; c) J. Jonas, S. Dage, The aromatic pathways of porphins, clorins and bacteriochlorins, Phys. Chem. Chem. Phys. 2 (10) (2000) 2145e2151, http://dx.doi.org/ 10.1039/b000260g. [2] a) F. Scala, E. Fattorusso, M. Menna, O. Taglialatela-Scafati, M. Tierney, M. Kaiser, D. Tasdemir, Mar. Drugs 8 (2010) 2162e2174, http://dx.doi.org/ 10.3390/md8072162; b) K. Hata, K. Baba, M. Kozawa, Chem. Pharm. Bull. 26 (1978) 2279. [3] M.D. Clift, R.J. Thomson, J. Am. Chem. Soc. 131 (2009) 14579e14583. [4] a) A. Idhayadhulla, R. Surendra Kumar, A.J.A. Nasser, J. Mex. Chem. Soc. 55 (4) (2011) 218e223; b) A. Idhayadhulla, R.S. Kumar, A.J.A. Nasser, A. Manilal, Bull. Chem. Soc. Ethiop. 26 (3) (2012) 429e435. [5] M.S. Mohamed, R.A. El-Domany, R.H.A. El-Hameed, Acta Pharm. 59 (2009) 145e158, http://dx.doi.org/10.2478/v10007-009-0016-9. [6] M.S. Mohamed, A.E. Rashad, M.E.A. Zaki, S.S. Fatahala, Acta Pharm. 55 (2005) 237e249. [7] A. Idhayadhulla, R. Surendra Kumar, A. Jamal Abdul Nasser, A. Manilal, Der Pharma Chem. 3 (4) (2011) 210e218. [8] G.S. Basarab, P.J. Hill, C.E. Garner, K. Hull, O. Green, B.A. Sherer, P.B. Dangel, J.I. Manchester, S. Bist, S. Hauck, F. Zhou, M. Uria-Nickelsen, R. Illingworth, R. Alm, M. Rooney, A.E. Eakin, Med. Chem. 57 (14) (2014) 6060e6082, http:// dx.doi.org/10.1021/jm500462x. [9] M. Biava, G.C. Porretta, G. Poce, A. De Logu, R. Meleddu, E. De Rossi, F. Manetti, M. Botta, Eur. J. Med. Chem. 51 (2009) 4734. [10] D. Deidda, G. Lampis, R. Fioravanti, M. Biava, G.C. Porretta, S. Zanetti, R. Pompei, Antimicrob. Agents Chemother. (1998) 3035e3037. [11] K.D. Asgaonkar, G.D. Mote, T.S. Chitre, Sci. Pharm. 82 (2014) 71e85, http:// dx.doi.org/10.3797/scipharm.1310-05. [12] R.A. Rane, S.S. Naphade, P. Kumar Bangalore, M.B. Palkar, M.S. Shaikh, R. Karpoormath, Bioorg. Med. Chem. Lett. 24 (14) (2014) 3079e3083. [13] C.C. Cain, D. Lee, R.H. Waldo III, A.T. Henry, E.J. Casida, M.C. Wani, M.E. Wall, N.H. Oberlies, J.O. Falkinham III, Antimicrob. Agents Chemother. 47 (2003) 2113. [14] C. Pullen, P. Schmitz, K. Meurer, D.D.V. Bamberg, S.S. Lohmann, F. de Castro, €llmann, F. Gollmick, U. Gr€ I. Groth, B. Schlegel, U. Mo afe, E. Leistner, Planta 216 (2002) 162. [15] L.R. Pagadala, L.D. Mukkara, S. Singireddi, A. Singh, V.R. Thummaluru, P.S. Jagarlamudi, R.S. Guttala, Y. Perumal, S. Dharmarajan, S.M. Upadhyayula, R. Ummanni, N. Ravirala, Eur. J. Med. Chem. 84 (2014) 118e126. [16] A. Mai, S. Massa, R. Pezzi, S. Simeoni, D. Rotili, A. Nebbioso, A. Scognamiglio, L. Altucci, P. Loidl, G. Brosch, J. Med. Chem. 48 (2005) 3344e3353. [17] R. Rango, S. Simeoni, D. Rotili, A. Caroli, G. Botta, G. Brosch, S. Massa, A. Mai, Eur. J. Med. Chem. 43 (2008) 621e631. [18] C.L. Fleming, T.D. Ashton, V. Gaur, S.L. McGee, F.M. Pfeffer, J. Med. Chem. 57 (3) (2014) 1132e1135, http://dx.doi.org/10.1021/jm401945k. [19] A.E. Eakin, O. Green, N. Hales, G.K. Walkup, S. Bist, A. Singh, G. Mullen, J. Bryant, K. Embrey, N. Gao, A. Breeze, D. Timms, B. Andrews, M. UriaNickelsen, J. Demeritt, J.T. Loch, K. Hull, A. Blodgett, R.N. Illingworth, B. Prince, P.A. Boriack-Sjodin, S. Hauck, L.J. MacPherson, H. Ni, B. Sherer, Antimicrob. Agents Chemother. 56 (2012) 1240. [20] Y.W. Han, G. Kashiwazaki, H. Morinaga, T. Matsumoto, K. Hashiya, T. Bando, Y. Harada, H. Sugiyama, Bioorg. Med. Chem. 21 (2013) 5436e5441. [21] A. Perdih, M. Hrast, H. Barreteau, S. Gobec, G. Wolber, T. Solmajer, Bioorg. Med. Chem. 22 (15) (2014) 4124e4134. [22] H. Zhao, L. Gartenmann, J. Dong, D. Spiliotopoulos, A. Caflisch, Bioorg. Med. Chem. Lett. 24 (11) (2014) 2493e2496.  [23] M. Chatzopoulou, A. Patsilinakos, T. Vallianatou, M.S. Prnova, S. Zakelj, R. Ragno, M. Stefek, A. Kristl, A. Tsantili-Kakoulidou, V.J. Demopoulos, Bioorg.

Med. Chem. 22 (7) (2014) 2194e2207. [24] F. Casuscelli, E. Ardini, N. Avanzi, E. Casale, G. Cervi, M. D'Anello, D. Donati, D. Faiardi, R.D. Ferguson, G. Fogliatto, A. Galvani, A. Marsiglio, D.G. Mirizzi, M. Montemartini, C. Orrenius, G. Papeo, C. Piutti, B. Salom, E.R. Felder, Bioorg. Med. Chem. 21 (23) (2013) 7364e7380. [25] D.Y. Duveau, A. Yasgar, Y. Wang, X. Hu, J. Kouznetsova, K.R. Brimacombe, A. Jadhav, A. Simeonov, C.J. Thomas, D.J. Maloney, Bioorg. Med. Chem. Lett. 24 (2) (2014) 630e635. [26] B. Brudeli, K.W. Andressen, L.R. Moltzau, N.O. Nilsen, F.O. Levy, J. Klaveness, Bioorg. Med. Chem. 21 (22) (2013) 7134e7145. [27] A.D. Jagtap, P.T. Chang, J.R. Liu, H.C. Wang, N.B. Kondekar, L.J. Shen, H.W. Tseng, G.S. Chen, J.W. Chern, Eur. J. Med. Chem. 85 (2014) 268e288. [28] H.C. Wang, A.D. Jagtap, P.T. Chang, J.R. Liu, C.P. Liu, H.W. Tseng, G.S. Chen, J.W. Chern, Eur. J. Med. Chem. (2014) 312e334. [29] J.J. Xue, Q.Y. Chen, M.Y. Kong, C.Y. Zhu, Z.R. Gen, Z.L. Wang, Eur. J. Med. Chem. 80 (2014) 1e7. [30] R. Silvestri, G. La Regina, G.D. Martino, M. Artico, O. Befani, M. Palumbo, E. Agostinelli, P. Turini, J. Med. Chem. 46 (6) (2003) 917e920, http:// dx.doi.org/10.1021/jm0256124. [31] M. Tao, C.H. Park, R. Bihovsky, G.J. Wells, J. Husten, M.A. Ator, R.L. Hudkins, Bioorg. Med. Chem. Lett 16 (4) (2006) 938e942. ~ oz Jans, H. Alzate-Morales, S. Cunha, L. Gano, R. Bergmann, [32] J. Caballero, C. Mun J. Steinbach, T. Kniess, Eur. J. Med. Chem. 58 (2012) 272e280. [33] A. Wiegard, W. Hanekamp, K. Griessbach, J. Fabian, M. Lehr, Eur. J. Med. Chem. 48 (2012) 153e163.
, [34] F. Piscitelli, A. Ligresti, G.L. Regina, V. Gatti, A. Brizzi, S. Pasquini, M. Allara M. Antonio, M. Carai, E. Novellino, G. Colombo, V.D. Marzo, F. Corelli, R. Silvestri, Eur. J. Med. Chem. 46 (11) (2011) 5641e5653. [35] J. Sasaki, K. Sano, M. Hagimori, M. Yoshikawa, M. Maeda, T. Mukai, Bioorg. Med. Chem. 22 (21) (2014) 6039e6046. [36] M.G. Brasca, M. Nesi, N. Avanzi, D. Ballinari, T. Bandiera, J. Bertrand, S. Bindi, G. Canevari, D. Carenzi, D. Casero, L. Ceriani, M. Ciomei, A. Cirla, M. Colombo, S. Cribioli, C. Cristiani, F.D. Vedova, G. Fachin, M. Fasolini, E.R. Felder, A. Galvani, A. Isacchi, D. Mirizzi, I. Motto, A. Panzeri, E. Pesenti, P. Vianello, P. Gnocchi, D. Donati, Bioorg. Med. Chem. 22 (17) (2014) 4998e5012. [37] K.C. Luk, M.E. Simcox, A. Schutt, K. Rowan, T. Thompson, Y. Chen, U. Kammlott, W. DePinto, P. Dunten, A. Dermatakis, Bioorg. Med. Chem. Lett. 14 (4) (2004) 913e917. [38] P. Pevarello, D. Fancelli, A. Vulpetti, R. Amici, M. Villa, V. Pittal
a, P. Vianello, A. Cameron, M. Ciomei, C. Mercurio, J.R. Bischoff, F. Roletto, M. Varasi, M.G. Brasca, Bioorg. Med. Chem. Lett. 16 (4) (2006) 1084e1090. [39] Y. Kashman, G. Koren-Goldshlager, M.D.G. Gravalos, M. Schleyer, Tetrahedron Lett. 40 (1999) 997e1000. [40] M.R. Heinrich, W. Steglich, M.G. Banwell, Y. Kashman, Tetrahedron 59 (2003) 9239e9247. [41] M. Egorov, B. Delpech, G. Aubert, T. Cresteil, M.C. Garcia-Alvarez, P. Collina, C. Marazano, Org. Biomol. Chem. 12 (9) (2014) 1518e1534, http://dx.doi.org/ 10.1039/c3ob42309c. [42] L. Shen, N. Xie, B. Yang, Y. Hu, Y. Zhang, Eur. J. Med. Chem. 85 (2014) 807e817. [43] L.A. Masterson, S.J. Croker, T.C. Jenkins, P.W. Howard, D.E. Thurston, Bioorg. Med. Chem. Lett. 14 (4) (2004) 901e904. [44] J.S. Moreno, D. Agas, M.G. Sabbieti, M.D. Magno, A. Migliorini, M.A. Loreto, Eur. J. Med. Chem. 57 (2012) 391e397. [45] W. Peng, D.C. Peltier, M.J. Larsen, P.D. Kirchhoff, S.D. Larsen, R.R. Neubig, D.J. Miller, J. Infect. Dis. 199 (2009) 950e957. [46] A.M. Almerico, A. Lauria, P. Diana, P. Barraja, G. Cirrincione, G. Dattolo, ARKIVOC iv (2000) 486e496. [47] X.Y. He, L. Lu, J. Qiu, P. Zou, F. Yu, X.K. Jiang, L. Li, S. Jiang, S. Liu, L. Xie, Bioorg. Med. Chem. 21 (23) (2013) 7539e7548. [48] S. Jiang, H. Lu, S. Liu, Q. Zhao, Y. He, A. K. Debnath 48, 11 (2004). 4349e4359. doi:10.1128/AAC.48.11.4349e4359.2004. [49] D.T. Mahajan, V.H. Masand, K.N. Patil, T.B. Hadda, V. Rastija, Med. Chem. Res. 22 (2013) 2284e2292, http://dx.doi.org/10.1007/s00044-012-0223-7. [50] a) Y. Sangnoi, O. Sakulkeo, S. Yuenyongsawad, A. Kanjana-opas, K. Ingkaninan, A. Plubrukarn, K. Suwanborirux, Mar. Drugs 6 (2008) 578e586; b) P. Srisukchayakul, C. Suwannachart, Y. Sangnoi, A. Kanjana-opas, S. Hosoya, A. Yokota, V. Arunpairojana, Int. J. Syst. Evol. Microbiol. 54 (2007) 2275e2279. [51] P.W. Okanya, K.I. Mohr, K. Gerth, R. Jansen, R. Muller, J. Nat. Prod. 74 (2011) 603e608. [52] B. Pacorel, S.C. Leung, A.V. Stachulski, J. Davies, L. Vivas, H. Lander, S.A. Ward, M. Kaiser, R. Brun, P.M. O'Neill, J. Med. Chem. 53 (2) (2010) 633e640, http:// dx.doi.org/10.1021/jm901216v. [53] L. Dyson, A.D. Wright, K.A. Young, J.A. Sakoff, A. McCluskey, Bioorg. Med. Chem. 22 (5) (2014) 1690e1699. [54] L. Zhang, Q. Zheng, Y. Yang, H. Zhou, X. Gong, S. Zhao, C. Fan, Eur. J. Med. Chem. 82 (2014) 139e151. [55] G. La Regina, R. Bai, A. Coluccia, V. Famiglini, S. Pelliccia, S. Passacantilli, C. Mazzoccoli, V. Ruggieri, L. Sisinni, A. Bolognesi, W.M. Rensen, A. Miele, M. Nalli, R. Alfonsi, L.D. Marcotullio, A. Gulino, A. Brancale, E. Novellino, G. Dondio, S. Vultaggio, M. Varasi, C. Mercurio, E. Hamel, P. Lavia, R. Silvestri, J. Med. Chem. 57 (15) (2014) 6531e6552. [56] K. Santosa, M. Laranjoa, A.M. Abrantesa, A.F. Britoa, C. Gonçalvesb, A.B.S. Ribeirob, M.F. Botelhoa, M.I.L. Soarese, A.S.R. Oliveirae Teresa, M.V.D. Pinhoe Meloe, Eur. J. Med. Chem. 79 (2014) 273e281. [57] Y. Liu, C. Zhang, H. Zhang, M. Li, J. Yuan, Y. Zhang, J. Zhou, H. Guo, L. Zhao,

S.S. Gholap / European Journal of Medicinal Chemistry 110 (2016) 13e31 Y. Du, L. Wang, L. Ren, Eur. J. Med. Chem. 93 (2015) 142e155. [58] S.A.F. Rostom, A.A. Bekhit, Eur. J. Med. Chem. 92 (2015) 712e722. [59] R. Chaniyara, S. Tala, C.W. Chen, P.C. Lee, R. Kakadiya, H. Dong, B. Marvania, C.H. Chen, T.C. Chou, T.C. Lee, A. Shah, T.L. Su, Eur. J. Med. Chem. 53 (2012) 28e40.  Guzm lez-Sa nchez, M.A. Cerbo  n, A. [60] J.D. Solano, I. Gonza an, M.A. Martínez~ iga, C. Alvarado, A. Quintero, Urbina, M.A. Vilchis-Reyes, E.C. Martínez-Zun E. Díaz, Eur. J. Med. Chem. 60 (2013) 350e359. ~o, M.F. Botelho, T.M.V.D. Pinhoe [61] M.I.L. Soares, A.F. Brito, M. Laranjo, J.A. Paixa Melo, Eur. J. Med. Chem. 60 (2013) 254e262. [62] A. Lauria, C. Patella, I. Abbate, A. Martorana, A.M. Almerico, Eur. J. Med. Chem. 55 (2012) 375e383. [63] A. Gangjeea, R.K. Pavanaa, W. Lia, E. Hamelb, C. Westbrookc, S.L. Mooberryc, Pharm. Res. 29 (11) (2012) 3033e3039, http://dx.doi.org/10.1007/s11095012-0816-3. [64] M.I. El-Gamal, C.H. Oh, Chem. Pharm. Bull. 62 (1) (2014) 25e34.
, A. Montalbano, D. Giallombardo, P. Barraja, [65] B. Parrino, A. Carbone, V. Spano A. Attanzio, L. Tesoriere, C. Sissi, M. Palumbo, G. Cirrincione, P. Diana, Eur. J. Med. Chem. 94 (2015) 367e377.
, A. Montalbano, P. Barraja, [66] B. Parrino, A. Carbone, C. Ciancimino, V. Spano G. Cirrincione, P. Diana, C. Sissi, M. Palumbo, O. Pinato, M. Pennati, G. Beretta, M. Folini, P. Matyus, B. Balogh, N. Zaffaroni, Eur. J. Med. Chem. 94 (2015) 149e162.

31

[67] M.G. Brasca, P. Gnocchi, M. Nesi, N. Amboldi, N. Avanzi, J. Bertrand, S. Bindi, G. Canevari, D. Casero, M. Ciomei, N. Colombo, S. Cribioli, G. Fachin, E.R. Felder, A. Galvani, A. Isacchi, I. Motto, A. Panzeri, D. Donati, Bioorg. Med. Chem. 23 (10) (2015) 2387e2407. [68] G.D. Ho, D. Tulshian, A. Bercovici, Z. Tan, J. Hanisak, S. Brumfield, J. Matasi, C.R. Heap, W.G. Earley, B. Courneya, R.J. Herr, X. Zhou, T. Bridal, D. Rindgen, S. Sorota, S.W. Yang, Bioorg. Med. Chem. Lett. 24 (2014) 4110e4113. [69] M.P. Winters, N. Subasinghe, M. Wall, E. Beck, M.R. Brandt, M.F.A. Finley, Y. Liu, M.L. Lubin, M.P. Neeper, N. Qin, C.M. Flores, Z. Sui, Bioorg. Med. Chem. Lett. 24 (2014) 2053e2056, http://dx.doi.org/10.1016/j.bmcl.2014.03.062. [70] Y.W. Chin, S.W. Lim, S.H. Kim, D.Y. Shin, Y.G. Suh, Y.B. Kim, Y.C. Kim, J. Kim, Bioorg. Med. Chem. Lett. 13 (2003) 79e81. zquez, C. Espinosa-Bustos, J. Soto-Delgado, J. Varela, [71] R.A. Tapia, C.O. Salas, K. Va lez, M. Paulino, Bioorg. Med. Chem. Lett. 24 E. Birriel, H. Cerecetto, M. Gonza (16) (2014) 3919e3922. [72] M. Biava, C. Battilocchio, G. Poce, S. Alfonso, S. Consalvi, A.D. Capua, V. Calderone, A. Martelli, L. Testai, L. Sautebin, A. Rossi, C. Ghelardini, L.D. Cesare Mannelli, A. Giordani, S. Persiani, M. Colovic, M. Dovizio, P. Patrignani, M. Anzini, Bioorg. Med. Chem. 22 (2) (2014) 772e786. [73] M. Biava, C. Battilocchio, G. Poce, S. Alfonso, S. Consalvi, G.C. Porretta, S. Schenone, V. Calderone, A. Martelli, L. Testai, C. Ghelardini, L.D.C. Mannelli, L. Sautebin, A. Rossi, A. Giordani, P. Patrignani, M. Anzini, Eur. J. Med. Chem. 58 (2012) 287e298.