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

A series of N-hydroxy-3-[3-(1-substituted-1H-benzoimidazol-2-yl)-phenyl]-acrylamides (5a–5ab) and N-hydroxy-3-[3-(1,4,5-trisubstituted-1H-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 EC50s 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 p21waf. Compound 5x displays efficacy in human tumor xenograft models.

Graphical abstractA 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.Figure optionsDownload full-size imageDownload as PowerPoint slide