C-6 aryl substituted 4-quinolone-3-carboxylic acids as inhibitors of hepatitis C virus

Yue Lei Chen; Jeana Zacharias; Robert Vince; Robert J. Geraghty; Zhengqiang Wang

doi:10.1016/j.bmc.2012.05.066

C-6 aryl substituted 4-quinolone-3-carboxylic acids as inhibitors of hepatitis C virus

Yue Lei Chen, Jeana Zacharias, Robert Vince, Robert J. Geraghty, Zhengqiang Wang

Center for Drug Design

Research output: Contribution to journal › Article › peer-review

17 Scopus citations

Abstract

Quinolone-3-carboxylic acid represents a highly privileged chemotype in medicinal chemistry and has been extensively explored as antibiotics and antivirals targeting human immunodeficiency virus (HIV) integrase (IN). Herein we describe the synthesis and anti-hepatitis C virus (HCV) profile of a series of C-6 aryl substituted 4-quinlone-3-carboxylic acid analogues. Significant inhibition was observed with a few analogues at low micromolar range against HCV replicon in cell culture and a reduction in replicon RNA was confirmed through an RT-qPCR assay. Interestingly, evaluation of analogues as inhibitors of NS5B in a biochemical assay yielded only modest inhibitory activities, suggesting that a different mechanism of action could operate in cell culture.

Original language	English (US)
Pages (from-to)	4790-4800
Number of pages	11
Journal	Bioorganic and Medicinal Chemistry
Volume	20
Issue number	15
DOIs	https://doi.org/10.1016/j.bmc.2012.05.066
State	Published - Aug 1 2012

Bibliographical note

Funding Information:
This research was supported by the Center for Drug Design at the University of Minnesota. We thank Dr. Guangxiang Luo at University of Kentucky for providing the Huh-7/HCV1b-Rluc replicon cells and Matthew Kesler for technical assistance.

Keywords

6-Aryl-4-quinolone-3-carboxylic acids
Hepatitis C virus inhibitors
NS5B polymerase

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title = "C-6 aryl substituted 4-quinolone-3-carboxylic acids as inhibitors of hepatitis C virus",

abstract = "Quinolone-3-carboxylic acid represents a highly privileged chemotype in medicinal chemistry and has been extensively explored as antibiotics and antivirals targeting human immunodeficiency virus (HIV) integrase (IN). Herein we describe the synthesis and anti-hepatitis C virus (HCV) profile of a series of C-6 aryl substituted 4-quinlone-3-carboxylic acid analogues. Significant inhibition was observed with a few analogues at low micromolar range against HCV replicon in cell culture and a reduction in replicon RNA was confirmed through an RT-qPCR assay. Interestingly, evaluation of analogues as inhibitors of NS5B in a biochemical assay yielded only modest inhibitory activities, suggesting that a different mechanism of action could operate in cell culture.",

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author = "Chen, {Yue Lei} and Jeana Zacharias and Robert Vince and Geraghty, {Robert J.} and Zhengqiang Wang",

note = "Funding Information: This research was supported by the Center for Drug Design at the University of Minnesota. We thank Dr. Guangxiang Luo at University of Kentucky for providing the Huh-7/HCV1b-Rluc replicon cells and Matthew Kesler for technical assistance. ",

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AU - Zacharias, Jeana

AU - Vince, Robert

AU - Geraghty, Robert J.

AU - Wang, Zhengqiang

N1 - Funding Information: This research was supported by the Center for Drug Design at the University of Minnesota. We thank Dr. Guangxiang Luo at University of Kentucky for providing the Huh-7/HCV1b-Rluc replicon cells and Matthew Kesler for technical assistance.

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AB - Quinolone-3-carboxylic acid represents a highly privileged chemotype in medicinal chemistry and has been extensively explored as antibiotics and antivirals targeting human immunodeficiency virus (HIV) integrase (IN). Herein we describe the synthesis and anti-hepatitis C virus (HCV) profile of a series of C-6 aryl substituted 4-quinlone-3-carboxylic acid analogues. Significant inhibition was observed with a few analogues at low micromolar range against HCV replicon in cell culture and a reduction in replicon RNA was confirmed through an RT-qPCR assay. Interestingly, evaluation of analogues as inhibitors of NS5B in a biochemical assay yielded only modest inhibitory activities, suggesting that a different mechanism of action could operate in cell culture.

KW - 6-Aryl-4-quinolone-3-carboxylic acids

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KW - NS5B polymerase

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C-6 aryl substituted 4-quinolone-3-carboxylic acids as inhibitors of hepatitis C virus

Abstract

Bibliographical note

Keywords

UN SDGs

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