1,5-Benzothiazepine Derivatives: Green Synthesis, In Silico and In Vitro Evaluation as Anticancer Agents.

Considering the importance of benzothiazepine pharmacophore, an attempt was carried out to synthesize novel 1,5-benzothiazepine derivatives using polyethylene glycol-400 (PEG-400)-mediated pathways. Initially, different chalcones were synthesized and then subjected to a cyclization step with benzothiazepine in the presence of bleaching clay and PEG-400. PEG-400-mediated synthesis resulted in a yield of more than 95% in less than an hour of reaction time. Synthesized compounds 2a-2j were investigated for their in vitro cytotoxic activity. Moreover, the same compounds were subjected to systematic in silico screening for the identification of target proteins such as human adenosine kinase, glycogen synthase kinase-3ß, and human mitogen-activated protein kinase 1. The compounds showed promising results in cytotoxicity assays; among the tested compounds, 2c showed the most potent cytotoxic activity in the liver cancer cell line Hep G-2, with an IC50 of 3.29 ± 0.15 µM, whereas the standard drug IC50 was 4.68 ± 0.17 µM. In the prostate cancer cell line DU-145, the compounds displayed IC50 ranges of 15.42 ± 0.16 to 41.34 ± 0.12 µM, while the standard drug had an IC50 of 21.96 ± 0.15 µM. In terms of structural insights, the halogenated phenyl substitution on the second position of benzothiazepine was found to significantly improve the biological activity. This characteristic feature is supported by the binding patterns on the selected target proteins in docking simulations. In this study, 1,5-benzothiazepines have been identified as potential anticancer agents which can be further exploited for the development of more potent derivatives.

Identification of N-Benzylated Indole Mannich Bases as Potential Anti TB Agents by Using Computational Studies and Molecular Hybridization Technique.

INTRODUCTION: Morbidity and mortality due to tuberculosis are rising steadily. Despite having efficient drugs and treatment protocols, microbial drug resistance often leads to treatment failure. Efforts to bring novel drugs to combat this menace are hampered by several issues including problems in gaining industry support, motivation and ethical issues clinical trials. Bedaquiline and Delaminid are the only novel drugs approved in the last three decades for treating TB. A few more molecules and drug combinations are still in clinical trials. One such drug is the BM212, a potent anti-TB agent which acts by a novel mechanism of action. METHODS: In the present study, we used virtual screening method with a combination of molecular hybridization technique to design N-benzylated Indole Mannich bases as potent anti-TB agent based on BM212 pharmacophore. The library of designed molecules was prepared and screened using BM212 model. The top 5 'hit' molecules were selected (with good TC score >1.15), synthesized and screened for anti TB activity by MABA assay method. RESULTS AND CONCLUSION: All the compounds showed excellent anti TB activity, of which 4 compounds have shown MIC ≤12.5 µg/mL. Our protocol could help in the designing of newer anti-TB agents with better bioactivity profile.