Synthesis of novel phenserine-based-selective inhibitors of butyrylcholinesterase for Alzheimer's disease

Four novel analogues (8-11) of cymserine (2) were synthesized by methods similar to those recently developed for the total syntheses of N-8-norphenserine (Yu, Q. S.; et al. J. Med. Chem. 1997, 40, 2895-2901) and N-1,N-8-bisnorphenserine (Yu, Q. S.; et al. J. Med. Chem. 1998, 41, 2371-2379). As our structure-activity studies predicted, these compounds are highly potent and selective inhibitors of human butyryleholinesterase (BChE) and will test the novel hypothesis that BChE inhibitors are useful in the treatment of Alzheimer's disease. In a similar manner, the same modifications that provided BChE selectivity were applied to the acetylcholinesterase (AChE)-selective inhibitor, tolserine (5), to provide the novel tolserine analogues 12-15. As predicted, these modifications altered the AChE-selective action of tolserine (5) to favor a lack of cholinesterase enzyme subtype selectivity.