Identification of Compound15(MMV1581361) as a PfATP4 Inhibitor with Transmission-Blocking Activity and In Vivo Efficacy in a SCID Mouse Model of Malaria

Focused structure–activity-relationship studies of MMV020136, 1, a whole-cell phenotypic screening hit originating from the Pathogen Box against the human malaria parasite, Plasmodium falciparum, led to the identification of compound 15 (MMV1581361). Compound 15 retained nanomolar activity against drug-sensitive, drug-resistant, and field isolates of Plasmodium falciparum blood-stage parasites. It was found to display a moderate rate-of-kill profile similar to pyrimethamine in vitro and efficacy in the humanized P. falciparumPf3D7^0087/N9 NODscidIL2Rγ^null mouse model at a single dose of 25 mg/kg, with similar kinetics to chloroquine. Furthermore, compound 15 demonstrated significant transmission-blocking potential, achieving 90% inhibition of male gamete exflagellation, a 98% reduction in mean oocyst intensity, and an 88% block in transmission. Mechanism-of-action studies revealed that compound 15 disrupts Na⁺ ion homeostasis in P. falciparum, indicating that it functions as a PfATP4 inhibitor. However, due to the resistance risk associated with the PfATP4 target and the presence of more advanced clinical candidates, further development of 15 into a viable antimalarial drug is currently deprioritised.