Optimization of 2,3-Dihydroquinazolinone-3-carboxamides as Antimalarials Targeting PfATP4

There is an urgent
need to populate the antimalarial clinical portfolio
with new candidates because of resistance against frontline antimalarials.
To discover new antimalarial chemotypes, we performed a high-throughput
screen of the Janssen Jumpstarter library against the Plasmodium falciparum asexual blood-stage parasite
and identified the 2,3-dihydroquinazolinone-3-carboxamide scaffold.
We defined the SAR and found that 8-substitution on the tricyclic
ring system and 3-substitution of the exocyclic arene produced analogues
with potent activity against asexual parasites equivalent to clinically
used antimalarials. Resistance selection and profiling against drug-resistant
parasite strains revealed that this antimalarial chemotype targets
PfATP4. Dihydroquinazolinone analogues were shown to disrupt parasite
Na+ homeostasis and affect parasite pH, exhibited a fast-to-moderate
rate of asexual kill, and blocked gametogenesis, consistent with the
phenotype of clinically used PfATP4 inhibitors. Finally, we observed
that optimized frontrunner analogue WJM-921 demonstrates oral efficacy
in a mouse model of malaria.