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

doi:10.1021/ml300464h

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 journal › Article › peer-review

53 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 language	English (US)
Pages (from-to)	517-521
Number of pages	5
Journal	ACS Medicinal Chemistry Letters
Volume	4
Issue number	6
DOIs	https://doi.org/10.1021/ml300464h
State	Published - Jun 13 2013

Keywords

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

ASJC Scopus subject areas

Biochemistry
Drug Discovery
Organic Chemistry

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10.1021/ml300464h

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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

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KW - High-throughput screening

KW - Human DHODH inhibitor

KW - Structure-activity relationship

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

Abstract

Keywords

ASJC Scopus subject areas

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