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

Priyabrata Das, Xiaoyi Deng, Liang Zhang, Michael G. Roth, Beatriz M A Fontoura, Margaret A. Phillips, Jef K. De Brabander

Research output: Contribution to journalArticlepeer-review

55 Scopus citations

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
StatePublished - Jun 13 2013

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

Fingerprint

Dive into the research topics of 'SAR-based optimization of a 4-quinoline carboxylic acid analogue with potent antiviral activity'. Together they form a unique fingerprint.

Cite this