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

Abstract

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−3β, 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.

Evaluation of 2,3-Dihydro-1,5-benzothiazepine Derivatives as Potential Tyrosinase Inhibitors: In Vitro and In Silico Studies

“…Currently, benzothiazepines are among the very broadly used pills in the treatment of cardiovascular diseases, including examples such as thiazesim, clentiazem, and diltiazem (Figure ). Benzothiazepine analogues have shown activity against various target proteins and are of particular interest for lead development …”

“…Benzothiazepine analogues have shown activity against various target proteins and are of particular interest for lead development. 19 Inspired by the therapeutic importance of the benzothiazepine scaffold 14 and in the perpetuation of our concern in creating new antityrosinase compounds, 8,10,14,20 herein, we report benzothiazepine as a potential TYR inhibitor. The novelty of this study lies in the investigation of the benzothiazepine scaffold for its potential tyrosinase inhibitory activity, which has not been previously explored.…”

“…Benzothiazepine analogues have shown activity against various target proteins and are of particular interest for lead development. 19 …”

Reactivity of curcumin and curcuminoid β-diketones with o-aminothiophenol: synthesis of 1,5-benzothiazepines

“…Although there is currently only one benzothiazepine structure marketed as a medicine, there are numerous scientific studies proposing new possible applications of very different benzothiazepine derivatives (1). Recently, five papers reporting the synthesis of 2,4-diaryl-1,5-benzothiazepines have been published (2,3,4,5,6) as well as a review (7). In these papers are reported some structures of representative drugs, in clinical use or undergoing clinical trials (Figure 1).…”