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Bioorg Med Chem. 2017 Feb 1;25(3):1030-1041. doi: 10.1016/j.bmc.2016.12.013. Epub 2016 Dec 9.

Design, synthesis and biological evaluation of 4'-aminochalcone-rivastigmine hybrids as multifunctional agents for the treatment of Alzheimer's disease.

Author information

1
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.
2
College of Chemistry and Pharmaceutical Engineering, Nanyang Normal University, Nanyang 473061, China.
3
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.
4
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.

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 Aβ1-42 aggregation and Cu2+-induced Aβ1-42 aggregation 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.

KEYWORDS:

Acetylcholinesterase inhibitors; Alzheimer’s disease; Aβ aggregation inhibitors; Chalcone carbamate derivatives; Monoamine oxidase B inhibitors; Multifunctional agents

PMID:
28011206
DOI:
10.1016/j.bmc.2016.12.013
[Indexed for MEDLINE]

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