Zhang_2025_Chin.Chem.Lett__110964

Alzheimer's disease (AD) is a common neurodegenerative disorder among the elderly population. There are currently no effective therapeutic drugs available, the multi-target-directed ligands (MTDLs) strategy has been considered as the promising approach. Given the structural diversity of natural products, Rivastigmine's pharmacophore was integrated with diverse natural product scaffolds to construct a combinatorial compound library. This library was subsequently screened and optimized to identify a novel butyrylcholinesterase (BuChE) inhibitor, compound 3c. The results showed that compound 3c exhibited favorable BuChE inhibitory activity (half-maximal inhibitory concentration (IC50)=0.43 micromol/L), potential anti-inflammatory potency, good Abeta1-42 aggregation inhibitory capacity and remarkable neuroprotective effects. The in vivo study exhibited that 3c significantly ameliorated AlCl3-induced zebrafish AD model and scopolamine-induced memory impairment. Collectively, compound 3c was the artificial intelligence (AI)-driven promising multifunctional agent with BuChE inhibition for the treatment of AD.