Design, Synthesis, and Evaluation of Multitarget-Directed Selenium-Containing Clioquinol Derivatives for the Treatment of Alzheimer鈥檚 Disease

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• 作者：Zhiren Wang ; Yali Wang ; Wenrui Li ; Fei Mao ; Yang Sun ; Ling Huang ; Xingshu Li
• 刊名：ACS Chemical Neuroscience
• 出版年：2014
• 出版时间：October 15, 2014
• 年：2014
• 卷：5
• 期：10
• 页码：952-962
• 全文大小：598K
• ISSN：1948-7193

文摘

A series of selenium-containing clioquinol derivatives were designed, synthesized, and evaluated as multifunctional anti-Alzheimer鈥檚 disease (AD) agents. In vitro examination showed that several target compounds exhibited activities such as inhibition of metal-induced A尾 aggregation, antioxidative properties, hydrogen peroxide scavenging, and the prevention of copper redox cycling. A parallel artificial membrane permeation assay indicated that selenium-containing clioquinol derivatives possessed significant blood-brain barrier (BBB) permeability. Compound 8a, with a propynylselanyl group linked to the oxine, demonstrated higher hydrogen peroxide scavenging and intracellular antioxidant activity than clioquinol. Furthermore, 8a exhibited significant inhibition of Cu(II)-induced A尾_1鈥?2 aggregation and was capable of disassembling the preformed Cu(II)-induced A尾 aggregates. Therefore, 8a is an excellent multifunctional promising compound for development of novel drugs for AD.

Keywords:

Alzheimer鈥檚 disease; selenium-containing clioquinol derivatives; antioxidative properties; inhibition of metal-induced A尾 aggregation