Design, synthesis and antiproliferative activities of novel benzamides derivatives as HDAC inhibitors

•Novel benzamides derivatives were synthesized and evaluated their antitumor activities against three human cancer cell lines.•All compounds demonstrated more or similar potent activities in comparison with MS-275.•Most compounds exhibited a reasonable inhibitory potency against HDAC1.•Compound 4a could be considered as a candidate HDAC inhibitor for further development.

Guided by the principle of nonclassical electronic isosterism and structural optimization, a series of novel HDAC inhibitors bearing a bicyclic heterocycle moiety were designed and synthesized based on the lead compound of MS-275. All the prepared compounds were evaluated for their in vitro antiproliferative activities against HCT-116, MCF-7 and A549 human cancer cell lines, all compounds exerted excellent antitumor activities. Moreover, the compound 4a exhibited an acceptable pharmacokinetic profile with bio-availability in rat of 76% and could be considered as a candidate compound for further development.

Graphical abstractA series of benzamides derivatives were designed and synthesized as highly potent HDAC inhibitors based on the lead compound of MS-275.Figure optionsDownload full-size imageDownload as PowerPoint slide