Synthesis, biological evaluation, and molecular docking analysis of novel linker-less benzamide based potent and selective HDAC3 inhibitors

[Display omitted] •A series of small molecule linker-less benzamides were designed and synthesized.•Two lead compounds 5e and 5f were found to be highly selective HDAC3 inhibitors.•Compound 5e (IC50 = 560 nM) ~ 46 and 33-fold selective for HDAC3 over HDAC2 and HDAC1.•5e, 5f showed excellent antiproliferative activity in cancer cells and least toxicity.•5e and 5f upregulated ac-H3K9 and ac-H4K12 in a dose-dependent manner in B16F10 cells.•5e and 5f induced apoptotic cell death in Annexin-V assay and caused G2/M phase cell cycle arrest.•5e and 5f revealed similar binding modes as that of CI994in silico concurrent with in vitro HDAC3 assay.•The results indicate 5e might serve as a potential anticancer therapeutic. A series of novel linker-less benzamides with different aryl and heteroaryl cap groups have been designed, synthesized, and screened as potent histone deacetylase (HDAC) inhibitors with promising anticancer activity. Two lead compounds 5e and 5f were found as potent and highly selective HDAC3 inhibitors over other Class-I HDACs and HDAC6. Compound 5e bearing a 6-quinolinyl moiety as the cap group was found to be a highly potent HDAC3 inhibitor (IC50 = 560 nM) and displayed 46-fold selectivity for HDAC3 over HDAC2, and 33-fold selectivity for HDAC3 over HDAC1. The synthesized compounds possess antiproliferative activities against different cancer cell lines and significantly less cytotoxic to normal cells. Molecular Docking studies of compounds 5e and 5f reveal a similar binding mode of interactions as CI994 at the HDAC3 active site. These observations agreed with the in vitro HDAC3 inhibitory activities. Significant enhancement of the endogenous acetylation level on H3K9 and H4K12 was found when B16F10 cells were treated with compounds 5e and 5f in a dose-dependent manner. The compounds induced apoptotic cell death in Annexin-V/FITC-PI assay and caused cell cycle arrest at G2/M phase of cell cycle in B16F10 cells. These compounds may serve as potential HDAC3 inhibitory anticancer therapeutics.