Discovery of novel 5-hydroxy-4-pyridone-3-carboxy acids as potent inhibitors of influenza Cap-dependent endonuclease

Bioorg Med Chem Lett. 2016 Oct 1;26(19):4739-4742. doi: 10.1016/j.bmcl.2016.08.038. Epub 2016 Aug 18.

Abstract

We report the discovery of a novel series of influenza Cap-dependent EndoNuclease (CEN) inhibitors based on the 4-pyridone-carboxylic acid (PYXA) scaffold, which were found from our chelate library. Our SAR research revealed the lipophilic domain to be the key to CEN inhibition. In particular, the position between the chelate and the lipophilic domain in the derivatives was essential for enhancing the potency. Our study, based on virtual modeling, led to the identification of 2y as a potent CEN inhibitor with an IC50 of 5.12nM.

Keywords: Anti-influenza drug; Cap-dependent endonuclease; Chelator; Pyridone; Virtual modeling.

MeSH terms

  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology*
  • Carboxylic Acids / chemistry
  • Crystallography, X-Ray
  • Drug Discovery*
  • Endonucleases / antagonists & inhibitors*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Inhibitory Concentration 50
  • Molecular Docking Simulation
  • Orthomyxoviridae / drug effects*
  • Pyridones / chemistry*
  • Structure-Activity Relationship

Substances

  • Antiviral Agents
  • Carboxylic Acids
  • Enzyme Inhibitors
  • Pyridones
  • 4-pyridone
  • Endonucleases