title: Tacrine-ferulic acid-nitric oxide (NO) donor trihybrids as potent, multifunctional acetyl- and butyrylcholinesterase inhibitors.
abstract: In search of multifunctional cholinesterase inhibitors as potential anti-Alzheimer drug candidates, tacrine-ferulic acid-NO donor trihybrids were synthesized and tested for their cholinesterase inhibitory activities, release of nitric oxide, vasodilator properties, cognition improving potency, and hepatotoxicity. All of the novel target compounds show higher in vitro cholinesterase inhibitory activity than tacrine. Three selected compounds (3a, 3f, and 3k) produce moderate vasorelaxation in vitro, which correlates with the release of nitric oxide. Compared to its non-nitrate dihybrid analogue (3u), the trihybrid 3f exhibits better performance in improving the scopolamine-induced cognition impairment (mice) and, furthermore, less hepatotoxicity than tacrine.
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Chen
authors.forename: Jianfei
authors.initials: J
authors.lastname: Sun
authors.forename: Lei
authors.initials: L
authors.lastname: Fang
authors.forename: Mei
authors.initials: M
authors.lastname: Liu
authors.forename: Sixun
authors.initials: S
authors.lastname: Peng
authors.forename: Hong
authors.initials: H
authors.lastname: Liao
authors.forename: Jochen
authors.initials: J
authors.lastname: Lehmann
authors.forename: Yihua
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001665:Binding Sites / Q000502:physiology; D001713:Biphenyl Compounds / Q000737:chemistry; D002091:Butyrylcholinesterase / Q000378:metabolism*; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003373:Coumaric Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008099:Liver / Q000378:metabolism / Q000473:pathology; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008958:Models, Molecular; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010851:Picrates / Q000737:chemistry; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship; D013619:Tacrine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects
chemical_list: D001713:Biphenyl Compounds; D002800:Cholinesterase Inhibitors; D003373:Coumaric Acids; D020030:Nitric Oxide Donors; D010851:Picrates; D009569:Nitric Oxide; D013619:Tacrine; C004931:1,1-diphenyl-2-picrylhydrazyl; D002091:Butyrylcholinesterase