Hu_2013_Bioorg.Med.Chem_21_676

Four series of novel heterodimers comprised of donepezil and huperzine A (HupA) fragments were designed, synthesized, and evaluated in search of potent acetylcholinesterase (AChE) inhibitors as potential therapeutic treatment for Alzheimer's disease. Heterodimers comprised of dimethoxyindanone (from donepezil), hupyridone (from HupA), and connected with a multimethylene linker, were identified as potent and selective inhibitors of AChE. Diastereomeric heterodimers (RS,S)-17b (with a tetramethylene linker) exhibited the highest potency of inhibition towards AChE with an IC(50) value of 9nM and no detectable inhibitory effect on butyrylcholinesterase at 1mM.