Lu_2022_Eur.J.Med.Chem_243_114729

Butyrylcholinesterase (BChE) is recently regarded as a biomarker in progressed Alzheimer's disease (AD), the development of selective BChE inhibitors has attracted a great deal of interest and may be a viable therapeutic strategy for AD. Previously, an aromatic tertiary amine derivative (S17-1001) was screened and validated as a selective BChE inhibitor. Structured-based molecular modification guided the synthesis of 43 analogs. Biological test of cholinesterase inhibition, in vitro blood brain barrier permeation assay, neurotoxicity assay and neuroprotective effects assay indicated two optimal compounds 17c and 19c. Both compounds showed selective BChE inhibitory (hBChE < 20 nM, eeAChE > 10 microM), good BBB permeation and primary cell safety. Besides, 17c can dose-response protect cell from Abeta(1-42) induced damage. It also demonstrated that 17c and 19c were able to restore cognitive impairment in vivo test. These data suggest that 17c and 19c represent promising candidate for follow-up in the drug-discovery process against AD.