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.
Bibliographical noteFunding 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.
Copyright 2013 Elsevier B.V., All rights reserved.
- 6-Aryl-4-quinolone-3-carboxylic acids
- Hepatitis C virus inhibitors
- NS5B polymerase