title: Design, synthesis and evaluation of novel tacrine-multialkoxybenzene hybrids as dual inhibitors for cholinesterases and amyloid beta aggregation.
abstract: A new series of tacrine-multialkoxybenzene hybrids (9a-9n) were designed, synthesized and evaluated as dual inhibitors of cholinesterases (ChEs) and self-induced β-amyloid (Aβ) aggregation. All the synthesized compounds had high acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory activity with IC₅₀ values at the nanomolar range, which were much better than tacrine alone. A Lineweaver-Burk plot and molecular modeling study showed that these hybrids targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. Besides, compounds 9a-9f with methylenedioxybenzene moiety showed higher self-induced Aβ aggregation inhibitory activity than a reference compound, curcumin. These compounds could be selected as multi-potent agents for further investigation to treat AD.
authors.affiliation: Sun Yat-sen University, Guangzhou, People's Republic of China.
authors.forename: Wen
authors.initials: W
authors.lastname: Luo
authors.forename: Yan-Ping
authors.initials: YP
authors.lastname: Li
authors.forename: Yan
authors.initials: Y
authors.lastname: He
authors.forename: Shi-Liang
authors.initials: SL
authors.lastname: Huang
authors.forename: Jia-Heng
authors.initials: JH
authors.lastname: Tan
authors.forename: Tian-Miao
authors.initials: TM
authors.lastname: Ou
authors.forename: Ding
authors.initials: D
authors.lastname: Li
authors.forename: Lian-Quan
authors.initials: LQ
authors.lastname: Gu
authors.forename: Zhi-Shu
authors.initials: ZS
authors.lastname: Huang
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D001554:Benzene / Q000737:chemistry*; D001665:Binding Sites; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003198:Computer Simulation; D015195:Drug Design; D007700:Kinetics; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism*; D013619:Tacrine / Q000737:chemistry*
chemical_list: D016229:Amyloid beta-Peptides; D002800:Cholinesterase Inhibitors; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D013619:Tacrine; D000110:Acetylcholinesterase; D001554:Benzene