Design, synthesis and biological evaluation of novel imidazole-based benzamide and hydroxamic acid derivatives as potent histone deacetylase inhibitors and anticancer agents

Abstract

New imidazoles bearing benzamide or hydroxamic acid group (as Zn binding groups) were designed and synthesized as HDAC inhibitors. Cytotoxicity of the compounds was evaluated against three types of cancer cells including HCT-116, A549, PC3 and a normal cell line (CHO). The inhibitory activities of the compounds were investigated against pan-HDAC isozymes including HDACs 1, 2, 3 and 6 and the activity of the most potent pan-HDAC inhibitors was evaluated against HDAC1. Most of the compounds showed significant cytotoxicity on cancer cells and did not show significant cytotoxicity on normal CHO cell line. Compound 7d showed promising antiproliferative activity against all the tested cancer cells, stronger than the other compounds. This compound showed significant cytotoxicity against HCT-116 cell line. Compounds 7c, 6a, 7b showed strong pan-HDAC inhibitory activity in HCT-116 cell line near equal to Entinostat. Compounds 7d and 7c inhibited HDAC1 strongly with IC50 values of 0.56 μM and 0.77 μM, respectively, which is comparable to Entinostat (IC50 = 0.49 μM) and is in good agreement with their cytotoxic effects. Annexin V-FITC/Propidium iodide staining assay in HCT116 cancer cells treated with compound 7d promoted cell apoptosis more potently compared to Entinostat as the reference compound. Molecular docking studies of compound 7d showed accepted binding mods of interaction between this compound and the HDAC1 enzyme.