Synthesis and inhibitory activity on hepatitis C virus RNA replication of 4-(1,1,1,3,3,3-hexafluoro-2-hydroxy-2-propyl)aniline analogs

Kenji Matsuno; Youki Ueda; Miwa Fukuda; Kenji Onoda; Minoru Waki; Masanori Ikeda; Nobuyuki Kato; Hiroyuki Miyachi

doi:10.1016/j.bmcl.2014.07.019

Synthesis and inhibitory activity on hepatitis C virus RNA replication of 4-(1,1,1,3,3,3-hexafluoro-2-hydroxy-2-propyl)aniline analogs

Bioorg Med Chem Lett. 2014 Sep 1;24(17):4276-80. doi: 10.1016/j.bmcl.2014.07.019. Epub 2014 Jul 15.

Authors

Kenji Matsuno¹, Youki Ueda², Miwa Fukuda³, Kenji Onoda³, Minoru Waki³, Masanori Ikeda², Nobuyuki Kato², Hiroyuki Miyachi³

Affiliations

¹ Medicinal and Bioorganic Chemistry, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530, Japan. Electronic address: matz@pharm.okayama-u.ac.jp.
² Department of Tumor Virology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan.
³ Medicinal and Bioorganic Chemistry, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530, Japan.

PMID: 25086684
DOI: 10.1016/j.bmcl.2014.07.019

Abstract

Using our recently developed assay system for full-genome-length hepatitis C virus (HCV) RNA replication in human hepatoma-derived Li23 cells (ORL8), we identified 4-(1,1,1,3,3,3-hexafluoro-2-hydroxy-2-propyl)aniline analog 1a as a novel HCV inhibitor. Structural modifications of 1a provided a series of sulfonamides 7 with much more potent HCV RNA replication-inhibitory activity than ribavirin. Compound 7a showed an additive anti-HCV effect in combination with standard anti-HCV therapy (IFN-α plus ribavirin). Since 7a generated reactive oxygen species (ROS) in the ORL8 system and its anti-HCV activity was blocked by vitamin E, its anti-HCV activity may be mediated at least in part by ROS.

Keywords: Anti-HCV agent; Full genome length; HCV RNA replication; Hepatitis C virus; ORL8.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antiviral Agents / chemical synthesis*
Antiviral Agents / chemistry
Antiviral Agents / pharmacology*
Cell Line, Tumor
Dose-Response Relationship, Drug
Hepacivirus / drug effects*
Hepacivirus / genetics*
Hepacivirus / growth & development
Humans
Microbial Sensitivity Tests
Molecular Structure
RNA, Viral / biosynthesis*
RNA, Viral / genetics
Reactive Oxygen Species / metabolism
Structure-Activity Relationship
Sulfonamides / chemical synthesis
Sulfonamides / chemistry*
Sulfonamides / pharmacology*
Virus Replication / drug effects
Virus Replication / genetics

Substances

Antiviral Agents
RNA, Viral
Reactive Oxygen Species
Sulfonamides