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Eur J Med Chem. 2015 Apr 13;94:218-28. doi: 10.1016/j.ejmech.2015.03.012. Epub 2015 Mar 6.

Discovery of HCV NS5B thumb site I inhibitors: core-refining from benzimidazole to indole scaffold.

Author information

1
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44, West Culture Road, 250012 Jinan, Shandong, PR China.
2
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44, West Culture Road, 250012 Jinan, Shandong, PR China. Electronic address: zhanpeng1982@sdu.edu.cn.
3
Department of Hepatic Diseases, Jinan Infectious Disease Hospital, Jingshi Road, 173, 250021 Jinan, Shandong, PR China. Electronic address: shdjxm@163.com.
4
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44, West Culture Road, 250012 Jinan, Shandong, PR China. Electronic address: xinyongl@sdu.edu.cn.

Abstract

Hepatitis C virus (HCV) NS5B RNA-depended-RNA-polymerase (RdRp) is an essential enzyme in HCV viral replication and has no functional equivalent in mammalian cells. Several classes of nucleoside and non-nucleoside inhibitors, targeting the different allosteric sites, have demonstrated efficacy in clinical trials. Compared to other allosteric sites, thumb site I is a more compelling allosteric target with a significant number of inhibitors in clinical trials. Among them, indole analogues are the most important series of NS5B thumb site I inhibitors with considerable antiviral activity. This review focuses on the discovery and development of indole inhibitors targeting on NS5B thumb site I. Five fundamental principles, the general structure-activity relationships (SARs) model of indole scaffold, were summarized, which could pave the way for further structural optimization of indole-based anti-HCV agents.

KEYWORDS:

Anti-viral; HCV; Heterocycle; Indole; RdRp; Thumb site I

PMID:
25768704
DOI:
10.1016/j.ejmech.2015.03.012
[Indexed for MEDLINE]

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