Publication Details

Structure−activity relationship studies of 2,8-disubstituted-1,5-naphthyridines, previously reported as potentinhibitors of Plasmodium falciarum (Pf) phosphatidylinositol-4-kinase β (PI4K), identified 1,5-naphthyridines with basic groups at8-position, which retained Plasmodium PI4K inhibitory activity butswitched primary mode of action to the host hemoglobindegradation pathway through inhibition of hemozoin formation.These compounds showed minimal off-target inhibitory activityagainst the human phosphoinositide kinases and MINK1 andMAP4K kinases, which were associated with the teratogenicity andtesticular toxicity observed in rats for the Pf PI4K inhibitor clinicalcandidate MMV390048. A representative compound from theseriesretained activity against field isolates and lab-raised drug-resistant strains of Pf. It was efficacious in the humanized NSG mousemalaria infection model at a single oral dose of 32 mg/kg. This compound wasnonteratogenic in the zebrafish embryo model ofteratogenicity and has a low predicted human dose, indicating that this series has the potential to deliver a preclinical candidate formalaria.