Thiazepine-Based Hybrids as Promising Anti-Colon Cancer Agents: Design, Synthesis, Computational and In Vitro Screening

Abstract

Novel thiazepine-based hybrids (9 a–d) were designed and synthesized to create lead molecules with exceptional anti-colon cancer efficacy. Analytical methods, including IR, NMR, and HR-MS, characterized the synthesized compounds. The in vitro colorectal study was carried out to compare the biological activity of newly developed compounds with the computational data. The tested compounds induced cytotoxicity in HT-29 cells for both 24 h and 48 h in a dose-dependent manner. However, compound 9 a induced cytotoxicity at much higher concentrations compared to the rest of the compounds. 9 b and 9 c caused 50 % cell death (compared to the untreated cells) at a dose of ~50 μM and 40 μM in case of 24-hour exposure, respectively. On the contrary, for 48 h exposure, both 9 b and 9 c induced 50 % cell death concerning untreated cells at a dose of around ~20 μM, whereas 9 d exhibited 50 % cell death at 5 μM in the case of 48 h exposure. In silico ADMET was also carried out to understand the pharmacokinetics and safety profiles of the drug candidates. We found some of the critical targets of these compounds, which eventually will be integral to exploring the mechanistic actions of these compounds in colon cancer.