Design, synthesis and evaluation of novel heterodimers of donepezil and huperzine fragments as acetylcholinesterase inhibitors

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 IC50 value of 9 nM and no detectable inhibitory effect on butyrylcholinesterase at 1 mM.

Heterodimers of donepezil and huperzine A fragments tethered with a tetramethylene linker exhibited high potency and selectivity towards acetylcholinesterase inhibition.Figure optionsDownload as PowerPoint slide