Discovery of novel butyrylcholinesterase inhibitors for treating Alzheimer's disease.

Alzheimer's disease (AD) is a common neurodegenerative disorder among the elderly, and BuChE has emerged as a potential therapeutic target. In this study, we reported the development of compound , a selective reversible BuChE inhibitor (BuChE IC = 0.049 μmol/L, BuChE IC = 0.066 μmol/L), identified through extensive virtual screening and lead optimization. Compound demonstrated favorable blood-brain barrier permeability, good drug-likeness property and pronounced neuroprotective efficacy. Additionally, exhibited significant therapeutic effects in zebrafish AD models and scopolamine-induced cognitive impairments in mice. Further, significantly improved cognitive function in APP/PS1 transgenic mice. Proteomics analysis demonstrated that markedly elevated the expression levels of very low-density lipoprotein receptor (VLDLR), offering valuable insights into its potential modulation of the Reelin-mediated signaling pathway. Thus, compound emerges as a novel and potent BuChE inhibitor for the treatment of AD, with significant implications for further exploration into its mechanisms of action and therapeutic applications.