Synthesis and biological evaluation of novel naphthoquinone [2,3-d] thiazole derivatives as potent 17β-HSD10 inhibitor.

A series of novel naphthoquinone[2,3-d] thiazole derivatives were designed as 17β-HSD10 inhibitors. Compound 14 emerged as the lead candidate, demonstrating potent 17β-HSD10 inhibition (IC50 = 6.33 μM) and favorable blood-brain barrier permeability. Molecular docking confirmed key interactions between its core scaffold and the 17β-HSD10 catalytic triad. In APP/PS1 mice, compound 14 significantly improved cognitive function without affecting 17β-HSD10 protein levels. It functionally inhibited 17β-HSD10, leading to rescued mitochondrial function (24% reduction in ROS, 76% increase in ATP, suppressed cytochrome c release), attenuated CDK5/p25 activation and Tau hyperphosphorylation, restored BDNF levels (58% increase in cortex), and reduced Aβ plaque load by approximately two-thirds. These results establish compound 14 as a multi-target neuroprotective agent for AD, concurrently ameliorating mitochondrial impairment, Tau pathology, and Aβ deposition through functional inhibition of 17β-HSD10.