title: Design, synthesis, and bioevaluation of benzamides: novel acetylcholinesterase inhibitors with multi-functions on butylcholinesterase, Aβ aggregation, and β-secretase.
abstract: Alzheimer's disease (AD) is a multifactorial syndrome with several target proteins contributing to its etiology. In this study, we conducted a structure-based design and successfully produced a series of new multi-site AChE inhibitors with a novel framework. Compound 2e, characterized by a central benzamide moiety linked to an isoquinoline at one side and acetophenone at the other, was the most potent candidate with K(i) of 6.47nM against human AChE. Particularly, it showed simultaneous inhibitory effects against BChE, Aβ aggregation, and β-secretase. We therefore conclude that compound 2e is a very promising multi-function lead for the treatment of AD.
authors.affiliation: Key Laboratory of Pesticide & Chemical Biology, College of Chemistry, Ministry of Education, Central China Normal University, Wuhan, PR China.
authors.forename: Da-Yong
authors.initials: DY
authors.lastname: Peng
authors.forename: Qi
authors.initials: Q
authors.lastname: Sun
authors.forename: Xiao-Lei
authors.initials: XL
authors.lastname: Zhu
authors.forename: Hong-Yan
authors.initials: HY
authors.lastname: Lin
authors.forename: Qiong
authors.initials: Q
authors.lastname: Chen
authors.forename: Ning-Xi
authors.initials: NX
authors.lastname: Yu
authors.forename: Wen-Chao
authors.initials: WC
authors.lastname: Yang
authors.forename: Guang-Fu
authors.initials: GF
authors.lastname: Yang
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000737:chemistry* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D002091:Butyrylcholinesterase / Q000737:chemistry* / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D007700:Kinetics; D062105:Molecular Docking Simulation; D017434:Protein Structure, Tertiary; D011806:Quinolinium Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C578974:1-(5-(4-((2-acetylphenyl)carbamoyl)phenoxy)pentyl)quinolin-1-ium; D016229:Amyloid beta-Peptides; D001549:Benzamides; D002800:Cholinesterase Inhibitors; D011806:Quinolinium Compounds; D002091:Butyrylcholinesterase; D053829:Amyloid Precursor Protein Secretases