Identification of Compound 15 (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. falciparum Pf3D70087/N9 NODscidIL2Rγnull 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.