Imidazole-based pinanamine derivatives: Discovery of dual inhibitors of the wild-type and drug-resistant mutant of the influenza A virus

Eur J Med Chem. 2016 Jan 27:108:605-615. doi: 10.1016/j.ejmech.2015.12.013. Epub 2015 Dec 15.

Abstract

We previously reported potent hit compound 4 inhibiting the wild-type influenza A virus A/HK/68 (H3N2) and A/M2-S31N mutant viruses A/WS/33 (H1N1), with its latter activity quite weak. To further increase its potency, a structure-activity relationship study of a series of imidazole-linked pinanamine derivatives was conducted by modifying the imidazole ring of this compound. Several compounds of this series inhibited the amantadine-sensitive virus at low micromolar concentrations. Among them, 33 was the most potent compound, which was identified as being active on an amantadine-sensitive virus through blocking of the viral M2 ion channel. Furthermore, 33 markedly inhibited the amantadine-resistant virus (IC50 = 3.4 μM) and its activity increased by almost 24-fold compared to initial compound, with its action mechanism being not M2 channel mediated.

Keywords: Dual inhibitory activity; Influenza A virus; M2 ion channel; Pinanamine derivatives.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiviral Agents / chemical synthesis
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology*
  • Cell Survival / drug effects
  • Dogs
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Drug Resistance, Viral / drug effects
  • Drug Resistance, Viral / genetics*
  • Imidazoles / chemical synthesis
  • Imidazoles / chemistry
  • Imidazoles / pharmacology*
  • Influenza A virus / drug effects*
  • Influenza A virus / genetics*
  • Madin Darby Canine Kidney Cells / drug effects
  • Madin Darby Canine Kidney Cells / virology
  • Microbial Sensitivity Tests
  • Molecular Structure
  • Mutation
  • Structure-Activity Relationship

Substances

  • Antiviral Agents
  • Imidazoles
  • pinanamine
  • imidazole