Discovery, Synthesis, and Biological Evaluation of a Novel Group of Selective Inhibitors of Filoviral Entry

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• 作者：Maria V. Yermolina ; Jizhen Wang ; Michael Caffrey ; Lijun L. Rong ; Duncan J. Wardrop
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：February 10, 2011
• 年：2011
• 卷：54
• 期：3
• 页码：765-781
• 全文大小：1241K
• 年卷期：v.54,no.3(February 10, 2011)
• ISSN：1520-4804

文摘

Herein, we report the development of an antifiloviral screening system, based on a pseudotyping strategy, and its application in the discovery of a novel group of small molecules that selectively inhibit the Ebola and Marburg glycoprotein (GP)-mediated infection of human cells. Using Ebola Zaire GP-pseudotyped HIV particles bearing a luciferase reporter gene and 293T cells, a library of 237 small molecules was screened for inhibition of GP-mediated viral entry. From this assay, lead compound 8a was identified as a selective inhibitor of filoviral entry with an IC₅₀ of 30 渭M. To analyze functional group requirements for efficacy, a structure鈭抋ctivity relationship analysis of this 3,5-disubstituted isoxazole was then conducted with 56 isoxazole and triazole derivatives prepared using 鈥渃lick鈥?chemistry. This study revealed that while the isoxazole ring can be replaced by a triazole system, the 5-(diethylamino)acetamido substituent found in 8a is required for inhibition of viral-cell entry. Variation of the 3-aryl substituent provided a number of more potent antiviral agents with IC₅₀ values ranging to 2.5 渭M. Lead compound 8a and three of its derivatives were also found to block the Marburg glycoprotein (GP)-mediated infection of human cells.