Synthesis, structure activity relationship and biological evaluation of a novel series of quinoline–based benzamide derivatives as anticancer agents and histone deacetylase (HDAC) inhibitors

Abstract

A novel series of quinoline-based benzamide derivatives was designed and synthesized as histone deacetylase (HDAC) inhibitors and anticancer agents. The cytotoxic activity of the synthesized compounds (10a-t) was evaluated against five human cancer cell lines including lung cancer cells (A549), colorectal adenocarcinoma cells (HT-29), breast cancer cells (MCF-7), colorectal cancer cells (HCT116) and ovarian cancer cells (A2780). All the compounds were more cytotoxic against HCT116 and HT-29 in comparison to the other human cancer cells. In general, compounds possessing a methyl group at position 2 of quinoline ring showed more cytotoxicity compared to those possessing an aryl group instead. Among the most potent 2-methyl quinolines, compounds possessing no substitution (10a) or small lipophilic groups (10b, 10c) on quinoline ring showed more cytotoxicity in HT-29 and HCT116 cell lines compared to those possessing bulky groups on the quinoline ring (10i, 10j). It can be attributed to steric hindrance of bulky groups in the binding site of HDAC enzyme or other targets. The most potent cytotoxic quinolines displayed remarkable enzyme inhibitory activity. The findings revealed that compounds 10a, 10b and 10c displayed strong enzyme inhibitory activity in HT-29 and HCT116 cells compared to the other tested quinolines which is consistent with their cytotoxic effect in these cell lines. Compounds 10a, the simplest compound and 10b (the methyl derivative of 10a), showed the most cytotoxicity as well as HDAC inhibitory potency, similar or comparable to the reference drug Entinostat. For investigating of interactions and stability of HDAC-ligand complex, docking studies, Molecular dynamics simulation and free binding energy calculation by MM-PBSA method were performed between HDAC 1/ HDAC3 and compound 10a and Entinostat.