Pyrazoleamide compounds are potent antimalarials that target Na+ homeostasis in intraerythrocytic Plasmodium falciparum

Nat Commun. 2014 Nov 25;5:5521. doi: 10.1038/ncomms6521.


The quest for new antimalarial drugs, especially those with novel modes of action, is essential in the face of emerging drug-resistant parasites. Here we describe a new chemical class of molecules, pyrazoleamides, with potent activity against human malaria parasites and showing remarkably rapid parasite clearance in an in vivo model. Investigations involving pyrazoleamide-resistant parasites, whole-genome sequencing and gene transfers reveal that mutations in two proteins, a calcium-dependent protein kinase (PfCDPK5) and a P-type cation-ATPase (PfATP4), are necessary to impart full resistance to these compounds. A pyrazoleamide compound causes a rapid disruption of Na(+) regulation in blood-stage Plasmodium falciparum parasites. Similar effect on Na(+) homeostasis was recently reported for spiroindolones, which are antimalarials of a chemical class quite distinct from pyrazoleamides. Our results reveal that disruption of Na(+) homeostasis in malaria parasites is a promising mode of antimalarial action mediated by at least two distinct chemical classes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphatases / genetics
  • Adenosine Triphosphatases / metabolism
  • Amides / pharmacology*
  • Antimalarials / pharmacology*
  • Benzimidazoles / pharmacology*
  • Erythrocytes / parasitology*
  • Female
  • Homeostasis / drug effects
  • Humans
  • Malaria / parasitology*
  • Male
  • Plasmodium berghei / drug effects
  • Plasmodium berghei / genetics
  • Plasmodium berghei / metabolism
  • Plasmodium falciparum / drug effects*
  • Plasmodium falciparum / enzymology
  • Plasmodium falciparum / genetics
  • Plasmodium falciparum / metabolism
  • Protein Kinases / genetics
  • Protein Kinases / metabolism
  • Protozoan Proteins
  • Pyrazoles / pharmacology*
  • Sodium / metabolism*


  • Amides
  • Antimalarials
  • Benzimidazoles
  • PA21A050
  • Protozoan Proteins
  • Pyrazoles
  • pyrazole
  • Sodium
  • Protein Kinases
  • calcium-dependent protein kinase
  • Adenosine Triphosphatases

Associated data

  • PubChem-Substance/221675649
  • PubChem-Substance/221675650
  • PubChem-Substance/221675651