Potent inhibitors of malarial P. Falciparum protein kinase G: Improving the cell activity of a series of imidazopyridines

Bioorg Med Chem Lett. 2019 Feb 1;29(3):509-514. doi: 10.1016/j.bmcl.2018.11.039. Epub 2018 Nov 20.

Abstract

Development of a class of bicyclic inhibitors of the Plasmodium falciparum cyclic GMP-dependent protein kinase (PfPKG), starting from known compounds with activity against a related parasite PKG orthologue, is reported. Examination of key sub-structural elements led to new compounds with good levels of inhibitory activity against the recombinant kinase and in vitro activity against the parasite. Key examples were shown to possess encouraging in vitro ADME properties, and computational analysis provided valuable insight into the origins of the observed activity profiles.

Keywords: Imidazopyridine; Malaria; Plasmodium falciparum; Protein kinase G; SAR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antimalarials / chemical synthesis
  • Antimalarials / chemistry
  • Antimalarials / pharmacology*
  • Cyclic GMP-Dependent Protein Kinases / antagonists & inhibitors*
  • Cyclic GMP-Dependent Protein Kinases / metabolism
  • Dose-Response Relationship, Drug
  • Imidazoles / chemical synthesis
  • Imidazoles / chemistry
  • Imidazoles / pharmacology*
  • Ligands
  • Molecular Structure
  • Parasitic Sensitivity Tests
  • Plasmodium falciparum / drug effects*
  • Plasmodium falciparum / enzymology
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Pyridines / chemical synthesis
  • Pyridines / chemistry
  • Pyridines / pharmacology*
  • Structure-Activity Relationship

Substances

  • Antimalarials
  • Imidazoles
  • Ligands
  • Protein Kinase Inhibitors
  • Pyridines
  • imidazopyridine
  • Cyclic GMP-Dependent Protein Kinases