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

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

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

4 Citations (Scopus)

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.

Original language	English
Pages (from-to)	4276-4280
Number of pages	5
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	24
Issue number	17
DOIs	https://doi.org/10.1016/j.bmcl.2014.07.019
Publication status	Published - Sept 1 2014

Keywords

Anti-HCV agent
Full genome length
HCV RNA replication
Hepatitis C virus
ORL8

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.bmcl.2014.07.019

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title = "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",

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",

author = "Kenji Matsuno and Youki Ueda and Miwa Fukuda and Kenji Onoda and Minoru Waki and Masanori Ikeda and Nobuyuki Kato and Hiroyuki Miyachi",

note = "Funding Information: This work was supported by the Drug Discovery for Intractable Infectious Diseases Project, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University from the Ministry of Education, Culture, Sports, Science and Technology (MEXT). The authors appreciate Mr. Yoshiaki Masuda of PharmaDesign Inc., Tokyo for the pK a calculations. The authors thank the Division of Instrumental Analysis, Okayama University for the NMR measurements.",

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doi = "10.1016/j.bmcl.2014.07.019",

language = "English",

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journal = "Bioorganic and Medicinal Chemistry Letters",

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T1 - 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

AU - Matsuno, Kenji

AU - Ueda, Youki

AU - Fukuda, Miwa

AU - Onoda, Kenji

AU - Waki, Minoru

AU - Ikeda, Masanori

AU - Kato, Nobuyuki

AU - Miyachi, Hiroyuki

N1 - Funding Information: This work was supported by the Drug Discovery for Intractable Infectious Diseases Project, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University from the Ministry of Education, Culture, Sports, Science and Technology (MEXT). The authors appreciate Mr. Yoshiaki Masuda of PharmaDesign Inc., Tokyo for the pK a calculations. The authors thank the Division of Instrumental Analysis, Okayama University for the NMR measurements.

PY - 2014/9/1

Y1 - 2014/9/1

N2 - 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.

AB - 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.

KW - Anti-HCV agent

KW - Full genome length

KW - HCV RNA replication

KW - Hepatitis C virus

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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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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