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
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U2 - 10.1021/ml300464h
DO - 10.1021/ml300464h
M3 - Article
C2 - 23930152
AN - SCOPUS:84879122914
SN - 1948-5875
VL - 4
SP - 517
EP - 521
JO - ACS Medicinal Chemistry Letters
JF - ACS Medicinal Chemistry Letters
IS - 6
ER -