Synthesis and docking studies of alkylene-linked dimers of (-)-huperzine A.

(-)-Huperzine A (5, HupA), an alkaloid isolated from the herb Huperzia serrata, is a potent, selective and reversible acetylcholinesterase (AchE) inhibitor. Based on the hypothesis with respect to two binding sites in the active gorge of AChE and the good example of bis-tacrine, it was predicted from the docking studies of alkylene-linked dimers of HupA that dimers 6 (n = 5, 7, 9) might have good AChE inhibitory activity. Therefore, six dimers with 7-12 methylene units as tethers were thus prepared. It was found that these dimers; were less potent than HupA in inhibition of AChE. The difference of the inhibitory potency between these dimers is coincident with the results of the docking studies.