Design, synthesis and biological activity of oxyevodiamine-based histone deacetylase 6 inhibitors.

Histone deacetylase 6 (HDAC6) was a potential target for Alzheimer's disease (AD). In this study, a series of novel oxyevodiamine-based HDAC6 inhibitors with a variety of linker moieties were designed, synthesized and evaluated. Compound 12 with a benzyl linker was identified as a high potent and selective HDAC6 inhibitor. It inhibited HDAC6 with an IC50 value of 6.2 nM and was more than 200 fold selectivity over HDAC1. It also had lower cytotoxicity and higher anti-H2O2 activity in vitro comparing with other derivatives. Compound 12 might be a good lead as novel HDAC6 inhibitor for the treatment of AD.