@article{e027433d27b04f7ba219b404cc685f5c,
title = "Pyrazoleamide compounds are potent antimalarials that target Na+ homeostasis in intraerythrocytic Plasmodium falciparum",
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.",
keywords = "3 amino 4 (4 fluorophenyl) n [4 (4 fluorophenyl) 1,3 dimethyl 1h pyrazol 5 yl]butanamide, adenosine triphosphatase, amide, antimalarial agent, calcium ion, chloroquine, n [4 (4 chloro 2 fluorophenyl) 1,3 dimethyl 1h pyrazol 5 yl) 2 (2 isopropyl 1h benzo[d]imidazol 1 yl]acetamide, n [4 (4 chloro 2 fluorophenyl) 3 (trifluoromethyl) 1 methyl 1h pyrazol 5 yl) 2 (2 isopropyl 1h benzo[d]imidazol 1 yl]acetamide, protein kinase, pyrazole derivative, sodium ion, unclassified drug, calcium-dependent protein kinase, protozoal protein, pyrazole, sodium, chemical compound, drug, enzyme activity, genome, homeostasis, malaria, parasite, animal experiment, animal model, antimalarial activity, antimalarial drug resistance, area under the curve, Article, cell pH, concentration response, controlled study, dose response, drug efficacy, drug potency, drug structure, drug synthesis, drug targeting, EC50, endoplasmic reticulum, erythrocyte, ex vivo study, female, gametocyte, gene mutation, gene sequence, gene transfer, growth inhibition, human, human cell, in vivo study, malaria falciparum, male, merozoite, molecule, nonhuman, parasite clearance, parasitemia, pH, Plasmodium, Plasmodium falciparum, Plasmodium vivax, schizont, sodium homeostasis, trophozoite, drug effects, enzymology, genetics, metabolism, parasitology, Plasmodium berghei, Adenosine Triphosphatases, Amides, Antimalarials, Erythrocytes, Female, Homeostasis, Humans, Malaria, Male, Protein Kinases, Protozoan Proteins, Pyrazoles, Sodium",
author = "Vaidya, {Akhil B.} and Morrisey, {Joanne M.} and Zhongsheng Zhang and Sudipta Das and Daly, {Thomas M.} and Otto, {Thomas D.} and Spillman, {Natalie J.} and Matthew Wyvratt and Peter Siegl and Jutta Marfurt and Grennady Wirjanata and Sebayang, {Boni F.} and Price, {Ric N.} and Arnab Chatterjee and Advait Nagle and Marcin Stasiak and Charman, {Susan A.} and I{\~n}igo Angulo-Barturen and Santiago Ferrer and {Bel{\'e}n Jim{\'e}nez-D{\'i}az}, Mar{\'i}a and Mart{\'i}nez, {Mar{\'i}a Santos} and Gamo, {Francisco Javier} and Avery, {Vicky M.} and Andrea Ruecker and Michael Delves and Kiaran Kirk and Matthew Berriman and Sandhya Kortagere and Jeremy Burrows and Erkang Fan and Bergman, {Lawrence W.}",
year = "2014",
doi = "10.1038/ncomms6521",
language = "English",
volume = "5",
pages = "1--10",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
}
