Effects of the aryl linker and the aromatic substituent on the anti-HCV activities of aryl diketoacid (ADK) analogues

Bioorg Med Chem Lett. 2008 Aug 15;18(16):4661-5. doi: 10.1016/j.bmcl.2008.07.008. Epub 2008 Jul 9.

Abstract

Based on our pharmacophore model of the aryl diketoacids (ADKs), we designed and prepared a series of novel ADK analogues, which showed potent inhibitory activities against the NS5B polymerase in the submicromolar range. Pharmacophore-guided docking study revealed that the antiviral activities of the ADKs are highly dependent upon the aryl linker as well as the size and position of the aromatic substituent. It is of another importance that, unlike previously reported ADKs, three ADK analogues synthesized in this study effectively blocked Hepatitis C Virus (HCV) replication in the replicon systems.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / chemical synthesis*
  • Antiviral Agents / pharmacology*
  • Chemistry, Pharmaceutical
  • Drug Design
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / pharmacology
  • Hepacivirus / metabolism
  • Inhibitory Concentration 50
  • Keto Acids / chemistry*
  • Keto Acids / pharmacology*
  • Models, Chemical
  • Molecular Conformation
  • Protein Binding
  • Replicon / drug effects
  • Viral Nonstructural Proteins / chemistry*
  • Viral Nonstructural Proteins / metabolism
  • Virus Replication

Substances

  • Antiviral Agents
  • Enzyme Inhibitors
  • Keto Acids
  • Viral Nonstructural Proteins
  • NS-5 protein, hepatitis C virus