Benzimidazole and imidazole inhibitors of histone deacetylases: Synthesis and biological activity

A series of imidazole and benzimidazole compounds were designed, synthesized, and found to be nanomolar inhibitors of human histone deacetylases, displaying activity in cellular and xenograft models. A series of N-hydroxy-3-[3-(1-substituted-1 H-benzoimidazol-2-yl)-phenyl]-acrylamides ( 5a– 5ab) and N-hydroxy-3-[3-(1,4,5-trisubstituted-1 H-imidazol-2-yl)-phenyl]-acrylamides ( 12a– s) were designed, synthesized, and found to be nanomolar inhibitors of human histone deacetylases. Multiple compounds bearing an N1-piperidine demonstrate EC 50s of 20–100 nM in human A549, HL60, and PC3 cells, in vitro and in vivo hyperacetylation of histones H3 and H4, and induction of p21 waf. Compound 5x displays efficacy in human tumor xenograft models.