Shaikh Faazil

Synthesis and biological evaluation of conformationally flexible as well as restricted dimers of monastrol and related dihydropyrimidones

A series of conformationally flexible and restricted dimers of monastrol as well as related dihydropyrimidones have been synthesized by employing one-pot Biginelli multicomponent reaction. These dimers have been evaluated for cytotoxic potency against selected human cancer cell lines and some of the compounds have exhibited more cytotoxic potency than the parent monastrol. Further, the DNA binding ability by thermal denaturation studies and antimicrobial activities of these compounds are also discussed.

Anti-tubercular agents. Part 8: synthesis, antibacterial and antitubercular activity of 5-nitrofuran based 1,2,3-triazoles.

A series of 5-nitrofuran-triazole conjugates were synthesized and evaluated for their antimicrobial activity against both Gram-positive and Gram-negative bacterial strains. All the compounds exhibited promising inhibition towards Gram-positive pathogenic strains, while mild inhibitory effects were observed towards Gram-negative bacterial strains. Some of the compounds 8a, 8b, 8e, 8f, 8h are most active among the series exhibiting MIC value of 1.17 μg/ml against different bacterial strains. The bactericidal activity is found to be in accordance with the bacterial growth inhibition data. Compound 8e was found to be equipotent to the standard drug Ciprofloxacin displaying MBC value of 1.17 μg/ml against the bacterial strain Bacillus subtilis. The compounds have also demonstrated promising antibacterial activity against the resistant strain MRSA and were found to be effective inhibitors of biofilm formation. The compound 8b exhibited excellent anti-biofilm activity with IC50 value as low as 0.8 μg/ml. These conjugates were also screened for antitubercular activity against Mycobacterium tuberculosis H37Rv strain. Compound 8e showed promising antitubercular activity with MIC value of 0.25 μg/ml. Most of these compounds are less toxic to normal mammalian cells than the widely used antibacterial drug Ciprofloxacin.

Apoptosis-inducing agents: a patent review (2010 – 2013)

Introduction: Apoptosis is an important and extensively studied pathway of programmed cell death, which is central to different physiological processes. Varied pathological implications, not limited to cancer and neurodegenerative diseases, occur if a slight dysfunction happens in the intricate apoptotic pathway. Therefore, it has become one of the prime molecular target for drug discovery and development particularly for diseases like cancer. Areas covered: As a promising drug target in the development of cancer chemotherapeutics, apoptosis has received extensive attention and hundreds of thousands of reports have been published. In the present review, the patents filed/published on apoptosis-inducing agents during the period of 2010 – 2013 have been compiled and discussed. Expert opinion: Most of the chemotherapeutics employed in cancer treatment leads to suppression of tumor via cell death irrespective of the mechanism of action or molecular target. No effective drug has emerged from the direct activation/inhibition of apoptotic regulatory proteins and of late some potential drugs, such as oblimersen, navitoclax, etc., targeting Bcl-2 family of proteins are under clinical trials. However, most of these molecules lacks efficacy accompanied with significant toxicity and resistance. Concerted efforts are required such as combination therapies and identification of newer selective inhibitor to overcome these limitations.

Design and Synthesis of Imidazo[2,1-b]thiazole–Chalcone Conjugates: Microtubule-Destabilizing Agents

A series of chalcone conjugates featuring the imidazo[2,1‐b]thiazole scaffold was designed, synthesized, and evaluated for their cytotoxic activity against five human cancer cell lines (MCF‐7, A549, HeLa, DU‐145 and HT‐29). These new hybrid molecules have shown promising cytotoxic activity with IC50 values ranging from 0.64 to 30.9 μM. Among them, (E)‐3‐(6‐(4‐fluorophenyl)‐2,3‐bis(4‐methoxyphenyl)imidazo[2,1‐b]thiazol‐5‐yl)‐1‐(pyridin‐2‐yl)prop‐2‐en‐1‐one (11 x) showed potent antiproliferative activity with IC50 values ranging from 0.64 to 1.44 μM in all tested cell lines. To investigate the mechanism of action, the detailed biological aspects of this promising conjugate (11 x) were carried out on the A549 lung cancer cell line. The tubulin polymerization assay and immunofluoresence analysis results suggest that this conjugate effectively inhibits microtubule assembly in A549 cells. Flow cytometric analysis revealed that this conjugate induces cell‐cycle arrest in the G2/M phase and leads to apoptotic cell death. This was further confirmed by Hoechst staining, activation of caspase‐3, DNA fragmentation analysis, and Annexin V–FITC assay. Moreover, molecular docking studies indicated that this conjugate (11 x) interacts and binds efficiently with the tubulin protein.

Synthesis and study of benzothiazole conjugates in the control of cell proliferation by modulating Ras/MEK/ERK-dependent pathway in MCF-7 cells

By applying a methodology, a series of benzothiazole-pyrrole based conjugates (4a-r) were synthesized and evaluated for their antiproliferative activity. Compounds such as 4a, 4c, 4e, 4g-j, 4m, 4n, 4o and 4r exhibited significant cytotoxic effect in the MCF-7 cell line. Cell cycle effects were examined for these conjugates at 2 μM as well as 4 μM concentrations and FACS analysis show an increase of G2/M phase cells with concomitant decrease of G1 phase cells thereby indicating G2/M cell cycle arrest by them. Interestingly 4o and 4r are effective in causing apoptosis in MCF-7 cells. Moreover, 4o showed down regulation of oncogenic expression of Ras and its downstream effector molecules such as MEK1, ERK1/2, p38 MAPK and VEGF. The apoptotic aspect of this conjugate is further evidenced by increased expression of caspase-9 in MCF-7 cells. Hence these small molecules have the potential to control both the cell proliferation as well as the invasion process in the highly malignant breast cancers.

L-Proline mediated synthesis of quinoxalines; evaluation of cytotoxic and antimicrobial activity

A simple, greener and highly efficient method for the synthesis of functionalized quinoxalines has been developed employing L-proline as a catalyst in water. To the best of our knowledge this transformation is achieved for the first time using an organic catalyst. A small library of quinoxaline–sulphonamide conjugates have been synthesized using this protocol. The newly synthesized conjugates have been tested for their cytotoxicity and antimicrobial activity against several bacterial strains including one fungal strain. The majority of the compounds have exhibited significant cytotoxicity as well as antimicrobial activity. Compounds 5a, 5b and 5d were found to be promising with respect to both cytotoxicity and antimicrobial activity.

Synthesis and anticancer potential of benzothiazole linked phenylpyridopyrimidinones and their diones as mitochondrial apoptotic inducers

A series of benzothiazole linked phenylpyridopyrimidinones (8a-g) and their diones (9a-g) have been designed, synthesized and evaluated for their anticancer activity. Among the series one of the conjugate 8b showed significant cytotoxicity against human cervical cancer cell line ME-180 with IC50 value of 4.01μM. This compound was tested on the cell cycle perturbations and DNA damage. Flow cytometry analysis revealed that the compound 8b showed drastic cell cycle perturbations due to concentration dependent increase in the sub-G0 phase in ME-180 cell line. DNA fragmentation and Hoechst staining reveals that this compound induced cell death by apoptosis. Further caspase-3 and loss of mitochondrial membrane potential suggested that the compound induces cell death by apoptosis.

Synthesis and mechanistic aspects of 2-anilinonicotinyl-pyrazolo[1,5-a]pyrimidine conjugates that regulate cell proliferation in MCF-7 cells via estrogen signaling.

A series of anilinonicotinyl linked pyrazolo[1,5-a]pyrimidine conjugates (6a-x) were synthesized and evaluated for their antiproliferative activity. Some of these conjugates exhibited promising cytotoxic effects in the MCF-7 cell line and among these 6a and 6c exhibited significant effects, apart from G2/M cell cycle arrest. Interestingly they showed profound effects on cyclin D1, Bcl-2 and survivin proteins that regulate breast cancer cell proliferation. Moreover, ER alpha protein expression was studied to understand regulatory role of these conjugates on estrogen activity in estrogen positive breast cancer cells like MCF-7 and compounds 6a and 6c reduced their activity.

Retracted: Synthesis and Cytotoxic Activity of 2‐Anilinopyridine‐3‐Acrylamides as Tubulin Polymerization Inhibitors

The following article Synthesis and Cytotoxic Activity of 2‐Anilinopyridine‐3‐Acrylamides as Tubulin Polymerization Inhibitors, by A. Kamal, Md. Ashraf, M. N. A. Khan, V. D. Nimbarte, S. Faazil, N. V. Subba Reddy, S. Taj, ChemMedChem, DOI: 10.1002/cmdc.201400036, published online on March 28, 2014 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the authors, the journal Editor‐in‐Chief, Natalia Ortúzar, and Wiley‐VCH Verlag GmbH & Co. KGaA. The retraction has been agreed due to concern over the reproducibility of the Western blot results reported in the article.In an attempt to develop potent anticancer agents, a series of 2-anilinonicotinyl-linked acrylamide conjugates were designed, synthesized, and evaluated for cytotoxic activity against various human cancer cell lines, anti-tubulin activity and cell-cycle effects. Among the series, compounds 6 d [(E)-N-(6-fluorobenzo[d]thiazol-2-yl)-3-(2-((3,4,5-trimethoxyphenyl)amino)pyridin-3-yl)acrylamide] and 6 p [(E)-3-(2-((4-methoxyphenyl)amino)pyridin-3-yl)-N-(6-nitrobenzo[d]thiazol-2-yl)acrylamide] showed promising cytotoxicity, specifically against the A549 human lung adenocarcinoma epithelial cell line, with GI50 values of 0.6±0.23 and 1.8±0.22 μM, respectively. Furthermore, cell-cycle perturbation studies by flow cytometry analysis indicated drastic cell-cycle effects in the G2 /M phase in this cell line followed by caspase-3 activation and apoptotic cell death. Molecular docking studies of the most potent compound, 6 d, revealed that this compound interacts with and binds efficiently in the active site of tubulin.