Design, synthesis and biological evaluation of novel coumarin-based benzamides as potent histone deacetylase inhibitors and anticancer agents

Abstract

Histone deacetylases (HDACs) are attractive therapeutic targets for the treatment of cancer and other diseases. It has four classes (I-IV), among them especially class I isozyme are involved in promoting tumor cells proliferation, angiogenesis, differentiation, invasion and metastasis and also viable targets for cancer therapeutics. A novel series of coumarin-based benzamides was designed and synthesized as HDAC inhibitors. The cytotoxic activity of the synthesized compounds (8a-u) was evaluated against six human cancer cell lines including HCT116, A2780, MCF7, PC3, HL60 and A549 and a single normal cell line (Huvec). We evaluated their inhibitory activities against pan HDAC and HDAC1 isoform. Four compounds (8f, 8q, 8r and 8u) showed significant cytotoxicity with IC₅₀ in the range of 0.53-57.59 μM on cancer cells and potent pan-HDAC inhibitory activity (consists of HDAC isoenzymes) (IC₅₀ = 0.80-14.81 μM) and HDAC1 inhibitory activity (IC₅₀ = 0.47-0.87 μM and also, had no effect on Huvec (human normal cell line) viability (IC₅₀ > 100 μM). Among them, 8u displayed a higher potency for HDAC1 inhibition with IC₅₀ value of 0.47 ± 0.02 μM near equal to the reference drug Entinostat (IC₅₀ = 0.41 ± 0.06 μM). Molecular docking studies and Molecular dynamics simulation of compound 8a displayed possible mode of interaction between this compound and HDAC1enzyme.

Keywords: 2-AminoBenzamide; Coumarin; Docking; Histone deacetylase inhibitors; Molecular dynamics.