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

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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 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
Volume4
Issue number6
DOIs
Publication statusPublished - Jun 13 2013

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Keywords

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

ASJC Scopus subject areas

  • Organic Chemistry
  • Drug Discovery
  • Biochemistry

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