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An innovative series of N-substituted piperazine-linked imidazothiazole derivatives 7(a-x) were synthesized, and their antitubercular effectiveness was evaluated. A three-step reaction sequence involving the condensation of 1,3-dichloroacetone and thiourea, coupling with substituted piperazines to give the intermediates 5(a-d) and cyclization with substituted α-bromoacetophenones produced the desired imidazothiazole derivatives 7(a-x) in excellent yields. In vitro screening of new derivatives against Mycobacterium tuberculosis H37Rv resulted in 7k (minimum inhibitory concentration [MIC]: 0.78 μg/mL) and 7g and 7h (MIC: 1.56 μg/mL) as potent hit compounds. Further, the docking studies of the promising compounds 7k, 7g, and 7h revealed that the best molecular interactions are with the DprE1 in complex with sulfonyl PBTZ of M. tuberculosis as the target protein (PDB ID: 6G83)., (© 2024 Wiley Periodicals LLC.) more...

We present N-imidazopyridine-noscapinoids, a new class of noscapine derivatives that bind to tubulin and exhibit antiproliferative activity against triple positive (MCF-7) and triple negative (MDA-MB-231) breast cancer cells. The N-atom of the isoquinoline ring of noscapine scaffold was altered in silico by coupling the imidazo [(Ye et al., 1998; Ke et al., 2000) 1,21,2-a] pyridine pharmacophore to rationally develop a series of N-imidazopyridine-noscapinoids (7-11) with high tubulin binding affinity. The predicted ΔG binding of the N-imidazopyridine-noscapinoids 7-11 varied from -27.45 to -36.15 kcal/mol, a much lower value than noscapine with ΔG binding -22.49 kcal/mol. The cytotoxicity of N-imidazopyridine-noscapinoids was evaluated using hormone dependent MCF-7, triple negative MDA-MB-231 breast cancer cell lines and primary breast cancer cells. The cytotoxicity of these compounds (represented as IC 50 concentration) ranges between 4.04 and 33.93 μM against breast cancer cells without affecting normal cells (IC 50 value > 952 μM). All the compounds (7-11) perturbed the cell cycle progression at G2/M phase and triggered apoptosis. Among all the N-imidazopyridine-noscapinoids, N-5-Bromoimidazopyridine-noscapine (9) showed promising antiproliferative activity and was selected for detailed investigation. The onset of apoptosis treated with 9 using MDA-MB-231 revealed morphological changes like cellular shrinkage, chromatin condensation, membrane blebbing, and apoptotic bodies formation. Along with elevated reactive oxygen species (ROS), there was a loss of mitochondrial membrane potential, suggesting induction of apoptosis to cancer cells. Compound 9 was also found to significantly regress the implanted tumour in nude mice as xenografts of MCF-7 cells without any apparent side effects after drug administration. We conclude that N-imidazopyridine-noscapinoids possess excellent potential as a promising drug for treating breast cancers., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.) more...

Lichen secondary metabolites are well explored medicinal agents with diverse pharmacological properties. One of the important antibiotic lichen secondary metabolites is usnic acid. Its diverse medicinal profiles prompted us to explore it as a potential antitubercular molecule. Towards this direction, continuing our efforts on the discovery and development of new analogs with potent antitubercular properties we designed, synthesized, and evaluated a set of 37 usnic acid enaminone-coupled aryl-n-hexanamides (3-39). The study yielded a 3,4-dimethoxyphenyl compound (13, 5.3 µM) as the most active anti-TB molecule. The docking studies were performed on 7 different enzymes to better understand the binding modes, where it was observed that compound 13 bound strongly with glucose dehydrogenase (Gscore: - 9.03). Further antibacterial investigations revealed compound 2 with potent inhibition on Salmonella typhi and Bacillus subtilis (MIC 3 µM) and MIC values of 7 and 14 µM on Streptococcus mutans and Escherichia coli respectively. Compound 19 (3-F-5-CF 3 -phenyl) displayed encouraging antibacterial profiles against E. coli, S. typhi and S. mutans with MIC values of 10 µM respectively. Interestingly, compound 20 (2,6-difluorophenyl) also displayed good antibacterial activity against E. coli with an MIC value of 6 µM. These encouraging pharmacological results will help for better designing and developing usnic acid-based semi-synthetic derivatives as potential antimicrobial agents. A set of 37 new usnic acid enaminone-coupled aryl-n-hexanamides were synthesized and evaluated as potential antimicrobial agents. Compound 13 was identified as the most active antitubercular molecule. 13 was further docked against 7 different enzymes of tuberculosis. The molecule displayed maximum binding energy with the enzyme Glucose dehydrogenase (Gscore: - 9.03), indicating that these hexanamides possibly act by inhibiting the glucose metabolic pathway of the bacterium. Surprisingly, the intermediate hexanoic acid 2 was identified as potent antibacterial agent, acting on both gram-positive and gram-negative bacterial strains (3-14 μM). The active compounds may be subjected to structural iterations to develop further leads., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.) more...

Noscapine is a phthalide isoquinoline alkaloid present in the latex of Papaver somniferum and has demonstrated potent antitumor activity in various cancer models. Structural changes in the core molecule of noscapine architecture have produced a number of potent analogs. We have recently synthesized the novel noscapine analogs (3, 4, and 5) with different functional groups appended at ninth position of natural noscapine. The anticancer activity of these compounds has been investigated using various human cancer cell lines such as HeLa (cervical cancer), DU-145 (prostate cancer), MCF-7 (breast cancer), and IMR-32 (neuroblastoma). One of the compounds in this series, 9-ethynyl noscapine (5), has demonstrated good anticancer activity against HeLa cells. Biological studies demonstrated that compound 5 decreased cell viability and colony formation in HeLa cells in a concentration dependent manner. To further uncover the mechanism in detail, we evaluated compound 5 effect on cell cycle progression, microtubule dynamics, and apoptosis. Cell cycle and western blotting analysis revealed that 9-ethynyl noscapine treatment resulted in cell cycle arrest at G2/M and decreased CDK1 and cyclinB1 protein expression. We also observed that 9-ethynyl noscapine (5) treatment leads to disruption in tubulin polymerization and induction of apoptosis by decreasing expression of bcl2, pro-caspase 3, and activation of cytochrome C. Taken together, our results indicate that 9-ethynyl noscapine (5) effectively supresses the growth of cervical cancer cells (HeLa) by disrupting tubulin polymerization, cell cycle progression leading to apoptosis., (© 2021 Wiley Periodicals LLC.) more...

The scaffold structure of noscapine (an antitussive plant alkaloid) was modified by inducting N-aryl methyl pharmacophore at C-9 position of the isoquinoline ring to rationally design and screened three novel 9-(N-arylmethylamino) noscapinoids, 15-17 with robust binding affinity with tubulin. The selected 9-(N-arylmethylamino) noscapinoids revealed improved predicted binding energy of -6.694 kcal/mol for 15, -7.118 kcal/mol for 16 and -7.732 kcal/mol for 17, respectively in comparison to the lead molecule (-5.135 kcal/mol). These novel derivatives were chemically synthesized and validated their anticancer activity based on cellular studies using two human breast adenocarcinoma, MCF-7 and MDA-MB-231, as well as with a panel of primary breast tumor cells. These derivatives inhibited cellular proliferation in all the cancer cells that ranged between 3.2 and 32.2 μM, which is 11.9 to 1.8 fold lower than that of noscapine. These novel derivatives effectively arrest the cell cycle in the G2/M phase followed by apoptosis and appearance of apoptotic cells. Thus, we conclude that 9-(N-arylmethyl amino) noscapinoids, 15-17 have a high probability to be a novel therapeutic agent for breast cancers., (© 2021 John Wiley & Sons A/S.) more...

We present a new class of derivatives of noscapine, 1,3-diynyl-noscapinoids of an antitussive plant alkaloid, noscapine based on our in silico efforts that binds tubulin and displays anticancer activity against a panel of breast cancer cells. Structure-activity analyses pointed the C-9 position of the isoquinoline ring which was modified by coupling of 1,3-diynyl structural motifs to rationally design and screened a series of novel 1,3-diynyl-noscapinoids (20-22) with robust binding affinity with tubulin. The selected 1,3-diynyl-noscapinoids, 20-22 revealed improved predicted binding energy of -6.568 kcal/mol for 20, -7.367 kcal/mol for 21 and -7.922 kcal/mol for 22, respectively in comparison to the lead molecule (-5.246 kcal/mol). These novel derivatives were chemically synthesized and validated their anticancer activity based on cellular studies using two human breast adenocarcinoma, MCF-7 and MDAMB-231, as well as with a panel of primary breast cancer cells isolated from patients. Interestingly, all these derivatives inhibited cellular proliferation in all the cancer cells that ranged between 6.2 to 38.9 μM, which is 6.7 to 1.5 fold lower than that of noscapine. Unlike previously reported derivatives of noscapine that arrests cells in the S-phase, these novel derivatives effectively inhibit proliferation of cancer cells, arrests cell cycle in the G2/M-phase followed by apoptosis and appearance of apoptotic cells. Thus, we conclude that 1,3-diynyl-noscapinoids have great potential to be a novel therapeutic agent for breast cancers., (Copyright © 2021 Elsevier Inc. All rights reserved.) more...

A library of 9-arylimino derivatives of noscapine was developed by coupling of Schiff base containing imine groups. Virtual screening using molecular docking with tubulin revealed three molecules, 12-14 that bind with high affinity. An improved predicted free energy of binding (FEB) of -5.390, -6.506 and -6.679 kcal/mol for the molecules 12-14 was found compared to noscapine (-5.135 kcal/mol). Furthermore, molecular dynamics simulation in combination with Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) revealed robust binding free energy of -166.03, -169.75 and -170.63 kcal/mol for the molecules 12, 13 and 14, respectively. These derivatives were strategically synthesized and experimentally validated for their anticancer activity. Tubulin binding assay revealed substantial binding of molecules 12-14 with purified tubulin. Further, their anticancer activity was demonstrated using two cancer cell lines (MCF-7 and MDAMB-231) and a panel of primary breast tumour cells. All these derivatives inhibited cellular proliferation in all the cancer cells that ranged between 30.1 and 5.8 µM, which is 1.7 to 7.52 fold lower than that of noscapine. Further, these novel derivatives arrest cell cycle in the G2/M-phase followed by induction of apoptosis. Thus, 9-arylimino noscapinoids 12-14 have a great potential to be a novel therapeutic agent for breast cancers. more...