Dong_2026_Eur.J.Med.Chem_316_119075

The pathogenesis of Alzheimer's disease (AD) is closely related with glycogen synthase kinase 3beta (GSK-3beta) and acetylcholinesterase (AChE). Our previous work verified that GL10a displayed superior GSK-3beta inhibitory and neuroprotective activities relative to Tideglusib. Accordingly, a molecular hybridization strategy was applied to design and synthesize a series of dual target inhibitors against GSK-3beta and AChE by conjugating GL10a and carbamate fragment of Rivastigmine's pharmacophore. After in vitro evaluations, the compound AJ-4 was screened as the most remarkable compound with potent inhibitory activities against GSK-3beta (IC(50): 4.7 nM) and AChE (IC(50): 2.97 microM). Meanwhile, in vitro and in vivo data revealed that the optimal compound AJ-4 with excellent enzyme selectivity could decrease amyloid precursor protein (APP) and phosphorylated Tau expressions and increase phosphorylated GSK-3beta levels. With favorable pharmacokinetic characteristics and tissue distribution, AJ-4 obviously ameliorated scopolamine-induced learning and memory impairments and alleviated hippocampal neuronal injury in AD mice. In conclusion, GSK-3beta/AChE dual inhibitors represent a promising strategy for developing multi-target anti-AD drugs.