Improved replicon cellular activity of non-nucleoside allosteric inhibitors of HCV NS5B polymerase: From benzimidazole to indole scaffolds

• Published in: Bioorganic & medicinal chemistry letters Vol. 16; no. 19; pp. 4987 - 4993
• Main Authors: Beaulieu, Pierre L., Gillard, James, Bykowski, Darren, Brochu, Christian, Dansereau, Nathalie, Duceppe, Jean-Simon, Haché, Bruno, Jakalian, Araz, Lagacé, Lisette, LaPlante, Steven, McKercher, Ginette, Moreau, Elaine, Perreault, Stéphane, Stammers, Timothy, Thauvette, Louise, Warrington, Jeff, Kukolj, George
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.10.2006; Elsevier
• Subjects: Allosteric inhibitors; Allosteric Regulation; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral; Antiviral agents; Benzimidazoles - pharmacology; Biological and medical sciences; Cell Line; HCV NS5B polymerase; Hepacivirus - drug effects; Hepatitis C virus; Humans; Indoles; Indoles - pharmacology; Inhibitory Concentration 50; Medical sciences; Pharmacology. Drug treatments; Replicon; Replicon - drug effects; RNA-Dependent RNA Polymerase - antagonists & inhibitors; Structure-Activity Relationship; Viral Nonstructural Proteins - antagonists & inhibitors; HCV NS5B polymerase; Allosteric inhibitors; Antiviral; Indoles; Hepatitis C virus; Replicon; Cell culture; Cyclohexane derivatives; RNA; Non nucleoside compound; Thiazole derivatives; Furan derivatives; Amides; Lipophilic compound; Structure activity relation; Chemical synthesis; Enzyme; Transferases; In vitro; RNA-directed RNA polymerase; Virus; Allosteric inhibitor; Nucleotidyltransferases; Benzimidazole derivatives; Replication; Flaviviridae; Indole derivatives; Hepacivirus
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2006.07.074

Benzimidazole-based allosteric inhibitors of the hepatitis C virus (HCV) NS5B polymerase were diversified to a variety of topologically related scaffolds. Replacement of the polar benzimidazole core by lipophilic indoles led to inhibitors with improved potency in the cell-based subgenomic HCV replicon system. Transposing the indole scaffold into a previously described series of benzimidazole–tryptophan amides generated the most potent inhibitors of HCV RNA replication in cell culture reported to date in this series (EC 50 ∼ 50 nM).