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) |
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Pages (from-to) | 467-479 |
Number of pages | 13 |
Journal | Bioorganic and Medicinal Chemistry |
Volume | 20 |
Issue number | 1 |
DOIs | |
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.
Keywords
- 2-Hydroxyisoquinoline-1,3-dione
- Hepatitis C virus (HCV)
- NS5B polymerase