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

Akhil B Vaidya,Jutta Marfurt,Susan A Charman,Grennady Wirjanata,Matthew Berriman,Santiago Ferrer,Joanne M Morrisey,María Santos Martínez,Kiaran Kirk,Sandhya Kortagere,Boni F Sebayang,Zhongsheng Zhang,Francisco Javier Gamo,Thomas M Daly,Thomas D Otto,Natalie J Spillman,Lawrence W Bergman,Erkang Fan,Andrea Ruecker,Vicky M Avery,Ric N Price,Arnab K Chatterjee ,Michael J Delves ,Marcin Stasiak ,A S Nagle ,Iñigo Angulo-Barturén ,Das S ,Jeremy N Burrows ,P K S Siegl ,Matthew J Wyvratt ,Marı́a Belén Jiménez-Dı́az

doi:10.1038/ncomms6521

Abstract

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.

Highlights

The quest for new antimalarial drugs, especially those with novel modes of action, is essential in the face of emerging drug-resistant parasites
Genetic and biochemical studies indicate that the pyrazoleamides are likely to affect a cationpumping P-type ATPase, resulting in rapid disruption of Na þ homeostasis in intraerythrocytic P. falciparum
Equal activity of PA21A092 was observed over a 48-h period against P. falciparum, regardless of the stage of parasites used in the assay, with effective concentration for 50% growth inhibition (EC50) values ranging from 5 to 13 nM (Fig. 1b)

Summary

Introduction

The quest for new antimalarial drugs, especially those with novel modes of action, is essential in the face of emerging drug-resistant parasites. We describe here our investigations of a new chemical class of antimalarial compounds with highly potent activity against P. falciparum and P. vivax, the most prevalent species causing human malaria. These compounds are active against parasites resistant to currently used antimalarials and are inhibitory to the onward development of the sexual stages of P. falciparum indicating their potential to be an effective means for treating malaria and for its transmission. Genetic and biochemical studies indicate that the pyrazoleamides are likely to affect a cationpumping P-type ATPase, resulting in rapid disruption of Na þ homeostasis in intraerythrocytic P. falciparum This mode of action is similar to a recent demonstration that NITD609 This mode of action is similar to a recent demonstration that NITD609 (ref. 9), an antimalarial spiroindolone under development with a very different chemical structure, disrupts Na þ homeostasis in malaria parasites[10]

Methods

Results

Conclusion