Design, synthesis and anti-Alzheimer's disease activity evaluation of dual 17β-HSD10 and CDK5/p25 inhibitors based on the naphtho[2,3-b]furan-4,9-dione scaffold.

A series of novel naphtho[2,3-b]furan-4,9-dione derivatives were designed and synthesized as dual inhibitors targeting 17β-HSD10 and CDK5/p25. Through in vitro enzymatic inhibition assays, blood-brain barrier permeability prediction, and molecular docking analysis, derivative 5l was identified as a lead candidate and selected for further in vivo evaluation. Pharmacodynamic assessment in APP/PS1 transgenic mice demonstrated that 5l significantly improved cognitive performance in the Morris water maze test. Mechanistic studies revealed that 5l not only effectively ameliorated mitochondrial function, but also attenuated aberrant Tau phosphorylation, reduced Aβ deposition, inhibited neuroinflammation, and enhanced neurotrophic support. Western blot results indicated that the neuroprotective effects of 5l were not mediated by modulating the expression levels of 17β-HSD10 and CDK5, but rather through inhibiting their enzymatic activities. Collectively, these findings demonstrate that this class of dual inhibitors counteracts key pathological features of Alzheimer's disease through multi-target and multi-pathway synergy, providing a solid experimental foundation for the development of novel therapeutic agents for AD.