title: Hybrids of oxoisoaporphine-tacrine congeners: novel acetylcholinesterase and acetylcholinesterase-induced β-amyloid aggregation inhibitors.
abstract: A series of dual binding site acetylcholinesterase (AChE) inhibitors have been designed, synthesized, and tested for their ability to inhibit AChE, butyrylcholinesterase (BChE), AChE-induced and self-induced β-amyloid (Aβ) aggregation. The new hybrids consist of a unit of 1-azabenzanthrone and a tacrine or its congener, connected through an oligomethylene linker containing an amine group at variable position. These hybrids exhibit high AChE inhibitory activity with IC(50) values in the nanomolar range in most cases. Moreover, five out of the 12 hybrids of this series, particularly those bearing a tetrahydroacridine moiety, exhibit a significant in vitro inhibitory activity toward the AChE-induced and self-induced Aβ aggregation, which makes them promising anti-Alzheimer drug candidates.
authors.affiliation: State Key Laboratory Cultivation Base for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry & Chemical Engineering of Guangxi Normal University, Guilin 541004, PR China.
authors.forename: Huang
authors.initials: H
authors.lastname: Tang
authors.forename: Li-Zhen
authors.initials: LZ
authors.lastname: Zhao
authors.forename: Hao-Tao
authors.initials: HT
authors.lastname: Zhao
authors.forename: Shi-Liang
authors.initials: SL
authors.lastname: Huang
authors.forename: Shu-Ming
authors.initials: SM
authors.lastname: Zhong
authors.forename: Jiang-Ke
authors.initials: JK
authors.lastname: Qin
authors.forename: Zhen-Feng
authors.initials: ZF
authors.lastname: Chen
authors.forename: Zhi-Shu
authors.initials: ZS
authors.lastname: Huang
authors.forename: Hong
authors.initials: H
authors.lastname: Liang
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism; D000682:Amyloid / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001060:Aporphines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001812:Blood-Brain Barrier / Q000378:metabolism; D002091:Butyrylcholinesterase / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D004593:Electrophorus; D006736:Horses; D006801:Humans; D008954:Models, Biological; D013619:Tacrine
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D001060:Aporphines; D002800:Cholinesterase Inhibitors; D013619:Tacrine; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase