Potent bicyclic inhibitors of malarial cGMP-dependent protein kinase: approaches to combining improvements in cell potency, selectivity and structural novelty

Bioorg Med Chem Lett. 2019 Oct 1;29(19):126610. doi: 10.1016/j.bmcl.2019.08.014. Epub 2019 Aug 9.

Abstract

Focussed studies on imidazopyridine inhibitors of Plasmodium falciparum cyclic GMP-dependent protein kinase (PfPKG) have significantly advanced the series towards desirable in vitro property space. LLE-based approaches towards combining improvements in cell potency, key physicochemical parameters and structural novelty are described, and a structure-based design hypothesis relating to substituent regiochemistry has directed efforts towards key examples with well-balanced potency, ADME and kinase selectivity profiles.

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

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bridged Bicyclo Compounds, Heterocyclic / chemistry
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology*
  • Cyclic GMP-Dependent Protein Kinases / antagonists & inhibitors*
  • Humans
  • Imidazoles / chemistry*
  • Malaria / drug therapy*
  • Malaria / enzymology
  • Malaria / parasitology
  • Models, Molecular
  • Molecular Docking Simulation
  • Plasmodium falciparum / drug effects*
  • Plasmodium falciparum / enzymology
  • Protein Conformation
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Pyridines / chemistry*

Substances

  • Bridged Bicyclo Compounds, Heterocyclic
  • Imidazoles
  • Protein Kinase Inhibitors
  • Pyridines
  • imidazopyridine
  • Cyclic GMP-Dependent Protein Kinases