New syntheses of rac-huperzine A and its rac-7-ethyl-derivative. Evaluation of several huperzine A analogues as acetylcholinesterase inhibitors

rac-Huperzine A, its rac-7-ethyl-derivative and two regioisomeric analogues have been prepared through synthetic sequences involving the elaboration o f the pyridone ring in a late stage, by reaction of an intermediate pyrroli dine enamine with propiolamide, which gave mixtures of regioisomeric pyrido ne derivatives; The acetylcholinesterase inhibitory activity of these and t wo other recently described 11-unsubstituted huperzine A analogues was dete rmined, the rac-7-ethyl analogue of huperzine A being the most active compo und, although it is about 12-fold less active than (-)-huperzine A. (C) 200 0 Elsevier Science Ltd. All rights reserved.