SAR-Based Optimization of a 4-Quinoline Carboxylic Acid Analogue with Potent Antiviral Activity

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• 作者：Priyabrata Das ; Xiaoyi Deng ; Liang Zhang ; Michael G. Roth ; Beatriz M. A. Fontoura ; Margaret A. Phillips ; Jef K. De Brabander
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2013
• 出版时间：June 13, 2013
• 年：2013
• 卷：4
• 期：6
• 页码：517-521
• 全文大小：283K
• 年卷期：v.4,no.6(June 13, 2013)
• ISSN：1948-5875

文摘

It is established that drugs targeting viral proteins are at risk of generating resistant strains. However, drugs targeting host factors can potentially avoid this problem. Herein, we report structure鈥揳ctivity relationship studies leading to the discovery of a very potent lead compound 6-fluoro-2-(5-isopropyl-2-methyl-4-phenoxyphenyl)quinoline-4-carboxylic acid (C44) that inhibits human dihydroorotate dehydrogenase (DHODH) with an IC₅₀ of 1 nM and viral replication of VSV and WSN-Influenza with an EC₅₀ of 2 nM and 41 nM. We also solved the X-ray structure of human DHODH bound to C44, providing structural insight into the potent inhibition of biaryl ether analogues of brequinar.

Keywords:

High-throughput screening; structure鈭抋ctivity relationship; antiviral; human DHODH inhibitor