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 P. 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 analogs with potent antiplasmodial activity equivalent to clinically used antimalarials. Resistance selection and profiling against drug-resistant parasite strains determined that this antimalarial chemotype targets PfATP4. Dihydroquinazolinone analogs were shown to perturb parasite cytosolic pH and Na+ levels, exhibited a fast-to-moderate rate of asexual kill, and block gametogenesis, consistent with the phenotype of clinically used PfATP4 inhibitors. Finally, we observed that the optimized frontrunner analog WJM-921 demonstrates oral efficacy in a mouse model of malaria.