Synthesis and evaluation of influenza A viral neuraminidase candidate inhibitors based on a bicyclo[3.1.0]hexane scaffold

Org Biomol Chem. 2016 Jul 6;14(27):6539-53. doi: 10.1039/c6ob00999a.

Abstract

This manuscript describes a novel class of derivatives based on a bicyclo[3.1.0]hexane scaffold, proposed as mimics of sialic acid in a distorted boat conformation that is on the catalytic pathway of neuraminidases (sialidases). A general synthetic route for these constrained-ring molecules was developed using a photochemical reaction followed by a Johnson-Corey-Chaykovsky cyclopropanation. Functionalization with the goal of occupying the 150-cavity was also exploited. Inhibition assays demonstrated low micromolar inhibition against both group-1 (H5N1) and group-2 (H9N2) influenza neuraminidase subtypes, indicating good affinity for the alpha and beta sialic acid mimics and 150-cavity-targeted derivatives. These results provide a validation of a bicyclo[3.1.0]hexane scaffold as a mimic of a distorted sialic acid bound in the neuraminidase active site during catalysis.

MeSH terms

  • Bridged Bicyclo Compounds / chemical synthesis*
  • Bridged Bicyclo Compounds / chemistry
  • Bridged Bicyclo Compounds / pharmacology*
  • Chemistry Techniques, Synthetic
  • Drug Design
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Influenza A Virus, H5N1 Subtype / enzymology*
  • Influenza A Virus, H9N2 Subtype / enzymology*
  • Models, Molecular
  • Neuraminidase / antagonists & inhibitors*
  • Neuraminidase / chemistry
  • Protein Conformation

Substances

  • Bridged Bicyclo Compounds
  • Enzyme Inhibitors
  • bicyclo(3.1.0)hexane
  • Neuraminidase