Download MendeleySAR Based Optimization of a 4-Quinoline Carboxylic Acid Analog with Potent Anti-Viral Activity.
Das, P., Deng, X., Zhang, L., Roth, M.G., Fontoura, B.M., Phillips, M.A., De Brabander, J.K.(2013) ACS Med Chem Lett 4: 517-521
- PubMed: 23930152
- DOI: https://doi.org/10.1021/ml300464h
- Primary Citation of Related Structures:
4IGH - PubMed Abstract:
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.
Organizational Affiliation:
Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390.
