Design and synthesis of novel histone deacetylase 6 inhibitors with benzyl-triazole as the core skeleton.

In the field of epigenetics, histone deacetylases (HDACs) are important members and well validated targets for anti-cancer drugs discovery. In this study, we designed and synthesized twenty-seven novel hydroxamic acid-based HDAC inhibitors (HDACis) with benzyl-triazole as the core skeleton. Most target compounds displayed excellent inhibition rates toward HDACs. Among them, compounds ZM-22 to ZM-27 with inhibition rates more than 90% toward HDACs exhibited potent inhibitory activity toward HDAC6, and ZM-23 possessed the best selectivity to HDAC6 over HDAC1. The high potency of compound ZM-23 toward HDAC6 was rationalized by molecular docking simulation. This series of compounds is worthy for further anti-cancer activity evaluation and structural optimization works.