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

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• 作者：Ganyuan Xiao^a ; Yan Li^a ; Xiaoming Qiang^a ; Rui Xu^a ; Yunxiaozhu Zheng^a ; Zhongcheng Cao^a ; Li Luo^a ; Xia Yang^a ; Zhipei Sang^b ; Fu Su^a ; ^{sufu@scu.edu.cn} ; Yong Deng^a ; ^{dengyong@scu.edu.cn}
• 关键词：Alzheimer&rsquo ; s disease ; Chalcone carbamate derivatives ; Multifunctional agents ; Acetylcholinesterase inhibitors ; Aβ aggregation inhibitors ; Monoamine oxidase B inhibitors
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2017
• 出版时间：1 February 2017
• 年：2017
• 卷：25
• 期：3
• 页码：1030-1041
• 全文大小：3965 K
• 卷排序：25

文摘

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 μM), 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 25 μM respectively, as well as acted as a selective monoamine oxidase B inhibitor (IC50 = 0.29 μM) 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.