Development of Thiazolidinedione-Based HDAC6 Inhibitors to Overcome Methamphetamine Addiction

Abstract

Thiazolidinedione is a five-membered heterocycle that is widely used in drug discovery endeavors. In this study, we report the design, synthesis, and biological evaluation of a series of thiazolidinedione-based HDAC6 inhibitors. In particular, compound <b>6b</b> exerts an excellent inhibitory activity against HDAC6 with an IC₅₀ value of 21 nM, displaying a good HDAC6 selectivity over HDAC1. Compound <b>6b</b> dose-dependently induces the acetylation level of <i>α</i>-tubulin via inhibition of HDAC6 in human neuroblastoma SH-SY5Y cell line. Moreover, compound <b>6b</b> efficiently reverses methamphetamine-induced morphology changes of SH-SY5Y cells via regulating acetylation landscape of <i>α</i>-tubulin. Collectively, compound <b>6b</b> represents a novel HDAC6-isoform selective inhibitor and demonstrates promising therapeutic potential for the treatment of methamphetamine addiction.