Design, Synthesis and Biological Evaluation of Novel Hydroxamic Acids Bearing Coumarin Moieties as Histone Deacetylase Inhibitors and Cytotoxic Agents

Abstract In this study, we successfully designed and synthesized a new series of coumarin-based hydroxamate derivatives as potent histone deacetylase (HDAC) inhibitors. Among them, several compounds showed strong inhibitory effects on whole-cell HDAC and exhibited moderate to significant antiproliferative activity against three human cancer cell lines, including MCF-7, A549 and SK-Lu-1. Notably, compounds 4c and 4d emerged as the most promising candidates. They inhibited HDAC with an IC₅₀ of 0.16 and 0.33 µM respectively, outperforming suberoylanilide hydroxamic acid (SAHA) (IC₅₀ = 0.63 µM) and demonstrated potent cytotoxicity against MCF-7 cancer cell line – from 1.2 to 6.8 times stronger than SAHA. Docking simulations further clarified their interactions with HDAC isoforms and explained its binding profile. Taken together, these findings highlight compound 4c and 4d as highly promising HDAC inhibitors with significant therapeutic potential in cancer treatment.