Design, synthesis and bioactivity evaluations of 8-substituted-quinoli- ne-2-carboxamide derivatives as novel histone deacetylase (HDAC) inhibitors

The inhibition of histone deacetylases (HDACs) has been considered a promising therapeutic strategy for treatment of many diseases, especially cancer. In the current study, a series of 8-substituted quinoline-2-carboxamide derivatives were designed and synthesized as potent HDAC inhibitors. The most potent com-pound 21 g (IC50 = 0.050 mu M) exhibited 3-fold greater HDAC inhibitory activity compared to the known HDAC inhibitor Vorinostat (IC50 = 0.137 mu M). Additionally, compound 21g exhibited low toxicity against normal cells (IC50 in HUVEC cell > 50 mu M) and showed good liver microsomal stability, therefore, may serve as a new lead compound for further development.