期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 25, 期 3, 页码 1030-1041出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2016.12.013
关键词
Alzheimer's disease; Chalcone carbamate derivatives; Multifunctional agents; Acetylcholinesterase inhibitors; A beta aggregation inhibitors; Monoamine oxidase B inhibitors
资金
- Chinese National Natural Science Foundation [20872099]
- Research Fund for the Doctoral Program of Higher Education [20110181110079]
- National Science and Technology Major Project on Key New Drug Creation and Manufacturing Program [2013ZX09301304-002]
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= 4.91 mu M),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 A beta(1-42) aggregation and Cu2+-induced A beta(1-42) aggregation by 89.5% and 79.7% at 25 mu M respectively, as well as acted as a selective monoamine oxidase B inhibitor (IC50 = 0.29 mu M) 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. (C) 2016 Elsevier Ltd. All rights reserved.
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