SummaryThere is an urgent need for new drugs to treat malaria, with broad therapeutic potential and novel modes of action, to widen the scope of treatment and to overcome emerging drug resistance. We describe the discovery of DDD107498, a compound with a potent and novel spectrum of antimalarial activity against multiple life-cycle stages of the parasite, with good pharmacokinetic properties, and an acceptable safety profile. DDD107498 demonstrates potential to address a variety of clinical needs, including single dose treatment, transmission blocking and chemoprotection. DDD107498 was developed from a screening programme against blood stage malaria parasites; its molecular target has been identified as translation elongation factor 2 (eEF2), which is responsible for the GTP-dependent translocation of the ribosome along mRNA, and is essential for protein synthesis. This discovery of eEF2 as a viable antimalarial drug target opens up new possibilities for drug discovery.

Ideally antimalarial drugs can be developed which target multiple life cycle stages, thus impacting prevention, treatment and transmission of disease. Here we introduce 4-(1H)-quinolone-3-diarylethers that are selectively potent inhibitors of the parasite’s mitochondrial cytochrome bc1 complex. These compounds are highly active against the primary human malarias (falciparum and vivax), targeting the parasite at both the liver and blood stages as well as the forms that are crucial to disease transmission: gametocytes ⇒ zygotes ⇒ ookinetes ⇒ oocysts. Chosen as the preclinical candidate, ELQ-300 has good oral bioavailability at efficacious dosages in mice, is metabolically stable, and is highly active in rodent malaria models. Given a low predicted dose in patients and a long predicted half-life, ELQ-300 offers the hope of a new molecule for the treatment, prevention and, ultimately, eradication of malaria.

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.