Design, synthesis and docking studies on benzamide derivatives as histone deacetylase inhibitors

A series of benzamide derivatives including two scaffolds were designed and synthesized as potential histone deacetylase inhibitors. Most of synthesized compounds showed moderate enzymatic potency at the same order of magnitude, and compound 12b possessed better potency to the positive control (3.8 μM vs 13.0 μM). It also showed a 50-fold increase in vitro anticancer activity against DU-145 cell-lines. Molecular docking studies were carried out and used to explain the structure-activity relationships observed in vitro. Then we found that the cavity surrounded by ASP104, HIS33, PRO34 and PHE155 may be crucial for the inhibitors’ activity. The docking results provide some useful information for future design of more potent inhibitors.