Racemic N1-norphenserine and its enantiomers: Unpredicted inhibition of human acetyl- and butyrylcholinesterase and β-amyloid precursor protein in vitro

The optically pure enantiomers of N'-norphenserine (15, 16) were synthesized and its racemate 17 was prepared by mixing equal parts of each enantiomer. (-)-N'-Norphenserine (15) was prepared by partial synthesis initiatedfrom the natural product, (-)-physostigmine (1). (+)-N'-Norphenserine (16) was prepared by total synthesis using the Julian oxindole route, with modifications. The in vitro inhibitory activities of 15-17 were quantified against human erythrocyte AChE and plasma BChE as well as against human neuroblastoma cell β-amyloid precursor protein secretion in cell culture. All were active. Racemic compound (17) with a high AChE and β-amyloid precursor protein inhibitory action may warrant further assessment in Alzheimer's disease models.