Design, synthesis and bioevaluation of novel N-heterocyclic hydroxamic acids as histone deacetylase inhibitors and their antitumor activity study†

Histone deacetylases (HDACs) represent a particularly intriguing focus in the discovery and advancement of anticancer drugs. In this study, we detail the design, synthesis, and evaluation of novel hydroxamic acids featuring a 1H-benzo[d]imidazole component as potent inhibitors of HDACs and potential anticancer agents. A total of 54 novel compounds were designed and synthesized. Biological assessment revealed that compounds 29c, 31c, and 33c were the most effective inhibitors of HDACs and demonstrated significant potential as anti-cancer agents. Furthermore, compound 31c exhibited a 3-fold higher inhibitory activity against the mixture of HDAC isoforms in HeLa cell nuclear extract compared to the reference compound SAHA. Finally, docking studies on HDAC2 and HDAC6 revealed hydrogen bonds and pi-stacking interactions between hydrophobic and hydrophilic residues on the binding pocket surface, particularly with benzimidazole rings and anilide substituents, which enhance the inhibitory potency of the studied compounds.