title: Design, synthesis and evaluation of novel heterodimers of donepezil and huperzine fragments as acetylcholinesterase inhibitors.
abstract: 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 9 nM and no detectable inhibitory effect on butyrylcholinesterase at 1mM.
authors.affiliation: Division of Life Science, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.
authors.forename: Yueqing
authors.initials: Y
authors.lastname: Hu
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.forename: Oormila
authors.initials: O
authors.lastname: Chandrashankra
authors.forename: Fanny C F
authors.initials: FC
authors.lastname: Ip
authors.forename: Nancy Y
authors.initials: NY
authors.lastname: Ip
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D000470:Alkaloids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D019281:Dimerization; D000077265:Donepezil; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D007189:Indans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012717:Sesquiterpenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000470:Alkaloids; D002800:Cholinesterase Inhibitors; D007189:Indans; D010880:Piperidines; D012717:Sesquiterpenes; C050426:huperzine A; D000077265:Donepezil; D000110:Acetylcholinesterase