Design and Synthesis of Novel Mitochondria-Targeted HDAC3 Inhibitors for the Treatment of Obesity

Abstract Obesity is closely associated with mitochondrial dysfunction, which impairs fatty acid oxidation and energy metabolism, yet currently available HDAC3 inhibitors have not been optimized to address these metabolic abnormalities. Herein, we developed a series of mitochondria-targeted HDAC3 inhibitors by incorporating a TPP moiety into the classical HDAC pharmacophore. Structure-based optimization identified H18 (IC50 = 45.4 nM) as the most promising candidate, exhibiting potent HDAC3 inhibitory activity together with preferential mitochondrial localization. H18 effectively suppressed lipid accumulation during 3T3-L1 adipocyte differentiation while restoring intracellular ATP levels and reducing oxidative stress. In diet-induced obese mice, H18 produced dose-dependent reductions in body weight gain, improved glucose tolerance, and insulin sensitivity and exhibited superior efficacy to BG45. Collectively, these findings identify H18 as a promising antiobesity lead compound and support the integration of mitochondrial targeting capability into HDAC3 inhibitor design as a promising strategy for obesity intervention.