SAR-based optimization of a 4-quinoline carboxylic acid analogue with potent antiviral activity

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29 Scopus citations


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 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.

Original languageEnglish (US)
Pages (from-to)517-521
Number of pages5
JournalACS Medicinal Chemistry Letters
Issue number6
Publication statusPublished - Jun 13 2013



  • Antiviral
  • High-throughput screening
  • Human DHODH inhibitor
  • Structure-activity relationship

ASJC Scopus subject areas

  • Organic Chemistry
  • Drug Discovery
  • Biochemistry

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