Design, synthesis and antitumor activity evaluation of novel benzamide HDAC inhibitors

In recent years, histone deacetylase (HDAC) has become one of the hottest and most effective targets for the treatment of cancer. In this work, we designed and synthesized a series of novel o-aminobenzamide based HDAC inhibitors and evaluated their antitumor properties in vitro. All 23 compounds obtained showed micromolar IC₅₀ values against A549 cells proliferation, and the most effective compound was 8 u (IC₅₀ = 0.165 μM). In vitro, 8 u showed potent antiproliferative activity against another three cancer cell lines, outperforming the approved drug Chidamide. Enzyme inhibition and western blot assays confirmed that 8 u was a selective inhibitor of HDAC1-3 isoforms. 8 u was able to induce apoptosis of A549 cells and arrest the tumor cells in G2/M phase. Moreover, 8 u significantly mitigated the migration A549 cells. All these results suggest that 8 u deserves further biological studies.