Discovery of 6'-chloro-N-methyl-5'-(phenylsulfonamido)-[3,3'-bipyridine]-5-carboxamide (CHMFL-PI4K-127) as a novel Plasmodium falciparum PI(4)K inhibitor with potent antimalarial activity against both blood and liver stages of Plasmodium

Eur J Med Chem. 2020 Feb 15:188:112012. doi: 10.1016/j.ejmech.2019.112012. Epub 2019 Dec 27.

Abstract

Starting from a bipyridine-sulfonamide scaffold, medicinal chemistry optimization leads to the discovery of a novel Plasmodium falciparum PI4K kinase (PfPI4K) inhibitor compound 15g (CHMFL-PI4K-127, IC50: 0.9 nM), which exhibits potent activity against 3D7 Plasmodium falciparum (P. falciparum) (EC50: 25.1 nM). CHMFL-PI4K-127 displays high selectivity against PfPI4K over human lipid and protein kinase. In addition, it exhibits EC50 values of 23-47 nM against a panel of the drug-resistant strains of P. falciparum. In vivo, the inhibitor demonstrates the favorable pharmacokinetic properties in both rats and mice. Furthermore, oral administration of CHMFL-PI4K-127 exhibits the antimalaria efficacy in both blood stage (80 mg/kg) and liver stage (1 mg/kg) of Plasmodium in infected rodent model. The results suggest that CHMFL-PI4K-127 might be a new potential drug candidate for malaria.

Keywords: Blood stage; Kinase inhibitor; Liver stage; Malaria; PI4K kinase.

MeSH terms

  • 1-Phosphatidylinositol 4-Kinase / antagonists & inhibitors*
  • 1-Phosphatidylinositol 4-Kinase / metabolism
  • Animals
  • Antimalarials / blood
  • Antimalarials / chemistry
  • Antimalarials / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Enzyme Inhibitors / blood
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Liver / drug effects*
  • Liver / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Molecular Structure
  • Parasitic Sensitivity Tests
  • Plasmodium falciparum / drug effects*
  • Plasmodium falciparum / metabolism
  • Pyridines / blood
  • Pyridines / chemistry
  • Pyridines / pharmacology*
  • Structure-Activity Relationship

Substances

  • Antimalarials
  • Enzyme Inhibitors
  • Pyridines
  • 1-Phosphatidylinositol 4-Kinase