Identification of halosalicylamide derivatives as a novel class of allosteric inhibitors of HCV NS5B polymerase

• Published in: Bioorganic & medicinal chemistry letters Vol. 18; no. 11; pp. 3173 - 3177
• Main Authors: Liu, Yaya, Donner, Pamela L., Pratt, John K., Jiang, Wen W., Ng, Teresa, Gracias, Vijaya, Baumeister, Steve, Wiedeman, Paul E., Traphagen, Linda, Warrior, Usha, Maring, Clarence, Kati, Warren M., Djuric, Stevan W., Molla, Akhteruzzaman
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.06.2008; Elsevier
• Subjects: Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral; Antiviral agents; Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Biological and medical sciences; Combinatorial Chemistry Techniques; Drug Design; HCV; HCV NS5B polymerase; Hepacivirus - drug effects; Hepatitis C; Humans; Medical sciences; Molecular Structure; Pharmacology. Drug treatments; Salicylamides - chemical synthesis; Salicylamides - chemistry; Salicylamides - pharmacology; Structure-Activity Relationship; Viral Nonstructural Proteins - antagonists & inhibitors; HCV NS5B polymerase; Antiviral; HCV; Hepatitis C; Enzyme; Transferases; Enzyme inhibitor; In vitro; Iodine Organic compounds; RNA-directed RNA polymerase; Infection; Virus; Allosteric inhibitor; Nucleotidyltransferases; Structure activity relation; Viral disease; Chlorine Organic compounds; Carboxamide; Flaviviridae; Chemical synthesis; Hepatitis C virus; Hepacivirus; Halogen Organic compounds; Viral hepatitis C
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2008.04.068

Halosalicylamide derivatives were evaluated as broad genotype inhibitors of HCV polymerase. Halosalicylamide derivatives were identified from high-throughput screening as potent inhibitors of HCV NS5B polymerase. The subsequent structure and activity relationship revealed the absolute requirement of the salicylamide moiety for optimum activity. Methylation of either the hydroxyl group or the amide group of the salicylamide moiety abolished the activity while the substitutions on both phenyl rings are acceptable. The halosalicylamide derivatives were shown to be non-competitive with respect to elongation nucleotide and demonstrated broad genotype activity against genotype 1–3 HCV NS5B polymerases. Inhibitor competition studies indicated an additive binding mode to the initiation pocket that is occupied by the thiadiazine class of compounds and an additive binding mode to the elongation pocket that is occupied by diketoacids, but a mutually exclusive binding mode with respect to the allosteric thumb pocket that is occupied by the benzimidazole class of inhibitors. Therefore, halosalicylamides represent a novel class of allosteric inhibitors of HCV NS5B polymerase.