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

Research output: Contribution to journalArticle

27 Citations (Scopus)

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

Fingerprint

Drug Delivery Systems
brequinar
Antiviral Agents
Lead compounds
Viral Proteins
Structure-Activity Relationship
Ether
Human Influenza
X-Rays
X rays
dihydroorotate dehydrogenase
quinoline-4-carboxylic acid
Lead

Keywords

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

ASJC Scopus subject areas

  • Organic Chemistry
  • Drug Discovery
  • Biochemistry

Cite this

SAR-based optimization of a 4-quinoline carboxylic acid analogue with potent antiviral activity. / Das, Priyabrata; Deng, Xiaoyi; Zhang, Liang; Roth, Michael G.; Fontoura, Beatriz M A; Phillips, Margaret A.; De Brabander, Jef K.

In: ACS Medicinal Chemistry Letters, Vol. 4, No. 6, 13.06.2013, p. 517-521.

Research output: Contribution to journalArticle

@article{2b8e859f73fa4ff5ab3eb213f3b113c2,
title = "SAR-based optimization of a 4-quinoline carboxylic acid analogue with potent antiviral activity",
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.",
keywords = "Antiviral, High-throughput screening, Human DHODH inhibitor, Structure-activity relationship",
author = "Priyabrata Das and Xiaoyi Deng and Liang Zhang and Roth, {Michael G.} and Fontoura, {Beatriz M A} and Phillips, {Margaret A.} and {De Brabander}, {Jef K.}",
year = "2013",
month = "6",
day = "13",
doi = "10.1021/ml300464h",
language = "English (US)",
volume = "4",
pages = "517--521",
journal = "ACS Medicinal Chemistry Letters",
issn = "1948-5875",
publisher = "American Chemical Society",
number = "6",

}

TY - JOUR

T1 - SAR-based optimization of a 4-quinoline carboxylic acid analogue with potent antiviral activity

AU - Das, Priyabrata

AU - Deng, Xiaoyi

AU - Zhang, Liang

AU - Roth, Michael G.

AU - Fontoura, Beatriz M A

AU - Phillips, Margaret A.

AU - De Brabander, Jef K.

PY - 2013/6/13

Y1 - 2013/6/13

N2 - 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.

AB - 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.

KW - Antiviral

KW - High-throughput screening

KW - Human DHODH inhibitor

KW - Structure-activity relationship

UR - http://www.scopus.com/inward/record.url?scp=84879122914&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84879122914&partnerID=8YFLogxK

U2 - 10.1021/ml300464h

DO - 10.1021/ml300464h

M3 - Article

VL - 4

SP - 517

EP - 521

JO - ACS Medicinal Chemistry Letters

JF - ACS Medicinal Chemistry Letters

SN - 1948-5875

IS - 6

ER -