title: Design, synthesis and biological evaluation of 4'-aminochalcone-rivastigmine hybrids as multifunctional agents for the treatment of Alzheimer's disease.
abstract: A series of 4'-aminochalcone-revastigmine hybrids were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer's disease. The results showed that most of these compounds exhibited good multifunctional activities. In particular, compound 6c displayed the best inhibitory potency on acetylcholinesterase (IC50=4.91μM), and significant antioxidative activity with a value 2.83-fold of Trolox. The kinetic analysis of AChE inhibition revealed that 6c showed mixed-type inhibition, binding simultaneously to the catalytic active site and peripheral anionic site of AChE. In addition, 6c inhibited self-induced Aβ1-42aggregation and Cu2+-induced Aβ1-42aggregation by 89.5% and 79.7% at 25μM respectively, as well as acted as a selective monoamine oxidase B inhibitor (IC50=0.29μM) and a selective biometal chelator. Furthermore, 6c could cross the blood-brain barrier in vitro. Based on these results, Compound 6c could be considered as a very promising lead compound for Alzheimer's disease.
authors.affiliation: Department of Medicinal Chemistry, Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
authors.forename: Ganyuan
authors.initials: G
authors.lastname: Xiao
authors.affiliation: Department of Medicinal Chemistry, Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Medicinal Chemistry, Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Qiang
authors.affiliation: Department of Medicinal Chemistry, Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Xu
authors.affiliation: Department of Medicinal Chemistry, Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
authors.forename: Yunxiaozhu
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Department of Medicinal Chemistry, Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
authors.forename: Zhongcheng
authors.initials: Z
authors.lastname: Cao
authors.affiliation: Department of Medicinal Chemistry, Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
authors.forename: Li
authors.initials: L
authors.lastname: Luo
authors.affiliation: Department of Medicinal Chemistry, Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Yang
authors.affiliation: College of Chemistry and Pharmaceutical Engineering, Nanyang Normal University, Nanyang 473061, China.
authors.forename: Zhipei
authors.initials: Z
authors.lastname: Sang
authors.affiliation: Department of Medicinal Chemistry, Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu 610041, China. Electronic address: sufu@scu.edu.cn.
authors.forename: Fu
authors.initials: F
authors.lastname: Su
authors.affiliation: Department of Medicinal Chemistry, Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu 610041, China. Electronic address: dengyong@scu.edu.cn.
authors.forename: Yong
authors.initials: Y
authors.lastname: Deng
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy*; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D047188:Chalcones / Q000737:chemistry / Q000494:pharmacology*; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D008995:Monoamine Oxidase / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000068836:Rivastigmine / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013552:Swine
chemical_list: D047188:Chalcones; D002800:Cholinesterase Inhibitors; D008996:Monoamine Oxidase Inhibitors; D008995:Monoamine Oxidase; D000110:Acetylcholinesterase; D000068836:Rivastigmine
keywords: Acetylcholinesterase inhibitors; Alzheimer’s disease; Aβ aggregation inhibitors; Chalcone carbamate derivatives; Monoamine oxidase B inhibitors; Multifunctional agents