Synthesis and biological evaluation of novel N-benzyltriazolyl-hydroxamate derivatives as selective histone deacetylase 6 inhibitors.

[Display omitted] • 27 novel N -benzyltriazolyl-hydroxamate derivatives were synthesized as selective HDAC6 inhibitor for Huntington's disease, autoimmune disease, and cancer. • Fluoro-substituted N -benzyltriazolyl-hydroxamate derivatives showed excellent HDAC6 enzyme activity and selectivity for HDAC6/ HDAC1. • Compound 4u could be a good candidate to treat HDAC6 enzyme-related diseases. Histone deacetylases (HDAC) regulate post-translational acetylation and the inhibition of these enzymes has emerged as an intriguing disease therapeutic. Among them, class IIb HDAC6 has the unique characteristic of mainly deacetylating cytoplasmic proteins, suggesting clinical applications for neurodegenerative diseases, inflammation, and cancer. In this study, we designed a novel N -benzyltriazolyl-hydroxamate scaffold based on the known HDAC6 inhibitors nexturastat A and tubastatin A. Among the 27 derivatives, 3-fluoro-4-((3-(2-fluorophenyl)-1 H -1,2,4-triazol-1-yl)methyl)- N -hydroxybenzamide 4u (HDAC6 IC 50 = 7.08 nM) showed nanomolar HDAC6 inhibitory activity with 42-fold selectivity over HDAC1. Structure-activity relationship (SAR) and computational docking studies were conducted to optimize the triazole capping group. Docking analysis revealed that the capping group aligned with the conserved L1 pocket of HDAC6 and was associated with subtype selectivity. Overall, our study explored the triazole-based biaryl capping group and its substitution and orientation, suggesting a rationale for the design of HDAC6-selective inhibitors. [ABSTRACT FROM AUTHOR]