The design, synthesis and biological evaluations of C-6 or C-7 substituted 2-hydroxyisoquinoline-1,3-diones as inhibitors of hepatitis C virus

Yue Lei Chen; Jing Tang; Matthew J. Kesler; Yuk Y. Sham; Robert Vince; Robert J. Geraghty; Zhengqiang Wang

doi:10.1016/j.bmc.2011.10.058

The design, synthesis and biological evaluations of C-6 or C-7 substituted 2-hydroxyisoquinoline-1,3-diones as inhibitors of hepatitis C virus

Yue Lei Chen
, Jing Tang
, Matthew J. Kesler
, Yuk Y. Sham
, Robert Vince
, Robert J. Geraghty
, Zhengqiang Wang

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

84 Scopus citations

Abstract

C7-Substituted 2-hydroxyisoquinoline-1,3-diones inhibit the strand transfer of HIV integrase (IN) and the reverse-transcriptase-associated ribonuclease H (RNH). Hepatitis C virus (HCV) NS5B polymerase shares a similar active site fold to RNH and IN, suggesting that N-hydroxyimides could be useful inhibitor scaffolds of HCV via targeting the NS5B. Herein we describe the design, chemical synthesis, replicon and biochemical assays, and molecular docking of C-6 or C-7 aryl substituted 2-hydroxyisoquinoline-1,3-diones as novel HCV inhibitors. The synthesis involved an improved and clean cyclization method, which allowed the convenient preparation of various analogs. Biological studies revealed that the C-6 analogs, a previously unknown chemotype, consistently inhibit both HCV replicon and recombinant NS5B at low micromolar range. Molecular modeling studies suggest that these inhibitors may bind to the NS5B active site.

Original language	English (US)
Pages (from-to)	467-479
Number of pages	13
Journal	Bioorganic and Medicinal Chemistry
Volume	20
Issue number	1
DOIs	https://doi.org/10.1016/j.bmc.2011.10.058
State	Published - Jan 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, Dr. Riccado Petrelli at University of Camerino, Italy, for providing 2 mA and the Minnesota Supercomputing Institute for computing resources.

UN SDGs

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

SDG 3 Good Health and Well-being

Keywords

2-Hydroxyisoquinoline-1,3-dione
Hepatitis C virus (HCV)
NS5B polymerase

Publisher link

10.1016/j.bmc.2011.10.058

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abstract = "C7-Substituted 2-hydroxyisoquinoline-1,3-diones inhibit the strand transfer of HIV integrase (IN) and the reverse-transcriptase-associated ribonuclease H (RNH). Hepatitis C virus (HCV) NS5B polymerase shares a similar active site fold to RNH and IN, suggesting that N-hydroxyimides could be useful inhibitor scaffolds of HCV via targeting the NS5B. Herein we describe the design, chemical synthesis, replicon and biochemical assays, and molecular docking of C-6 or C-7 aryl substituted 2-hydroxyisoquinoline-1,3-diones as novel HCV inhibitors. The synthesis involved an improved and clean cyclization method, which allowed the convenient preparation of various analogs. Biological studies revealed that the C-6 analogs, a previously unknown chemotype, consistently inhibit both HCV replicon and recombinant NS5B at low micromolar range. Molecular modeling studies suggest that these inhibitors may bind to the NS5B active site.",

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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, Dr. Riccado Petrelli at University of Camerino, Italy, for providing 2 mA and the Minnesota Supercomputing Institute for computing resources. ",

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AU - Sham, Yuk Y.

AU - Vince, Robert

AU - Geraghty, Robert J.

AU - Wang, Zhengqiang

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N2 - C7-Substituted 2-hydroxyisoquinoline-1,3-diones inhibit the strand transfer of HIV integrase (IN) and the reverse-transcriptase-associated ribonuclease H (RNH). Hepatitis C virus (HCV) NS5B polymerase shares a similar active site fold to RNH and IN, suggesting that N-hydroxyimides could be useful inhibitor scaffolds of HCV via targeting the NS5B. Herein we describe the design, chemical synthesis, replicon and biochemical assays, and molecular docking of C-6 or C-7 aryl substituted 2-hydroxyisoquinoline-1,3-diones as novel HCV inhibitors. The synthesis involved an improved and clean cyclization method, which allowed the convenient preparation of various analogs. Biological studies revealed that the C-6 analogs, a previously unknown chemotype, consistently inhibit both HCV replicon and recombinant NS5B at low micromolar range. Molecular modeling studies suggest that these inhibitors may bind to the NS5B active site.

AB - C7-Substituted 2-hydroxyisoquinoline-1,3-diones inhibit the strand transfer of HIV integrase (IN) and the reverse-transcriptase-associated ribonuclease H (RNH). Hepatitis C virus (HCV) NS5B polymerase shares a similar active site fold to RNH and IN, suggesting that N-hydroxyimides could be useful inhibitor scaffolds of HCV via targeting the NS5B. Herein we describe the design, chemical synthesis, replicon and biochemical assays, and molecular docking of C-6 or C-7 aryl substituted 2-hydroxyisoquinoline-1,3-diones as novel HCV inhibitors. The synthesis involved an improved and clean cyclization method, which allowed the convenient preparation of various analogs. Biological studies revealed that the C-6 analogs, a previously unknown chemotype, consistently inhibit both HCV replicon and recombinant NS5B at low micromolar range. Molecular modeling studies suggest that these inhibitors may bind to the NS5B active site.

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KW - NS5B polymerase

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The design, synthesis and biological evaluations of C-6 or C-7 substituted 2-hydroxyisoquinoline-1,3-diones as inhibitors of hepatitis C virus

Abstract

Bibliographical note

UN SDGs

Keywords

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