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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-activity 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 IC 50 of 1 nM, and viral replication of VSV and WSN-Influenza with an EC 50 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 analogs of brequinar.

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