Lead optimization of a pyrrole-based dihydroorotate dehydrogenase inhibitor series for the treatment of malaria

Malaria puts at risk nearly half the world's population and causes high mortality in sub-Saharan Africa, while drug resistance threatens current therapies. The pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH) is a validated target for malaria treatment based on our finding that triazolopyrimidine DSM265 (; 1; ) showed efficacy in clinical studies. Herein, we describe optimization of a pyrrole-based series identified using a target-based DHODH screen. Compounds with nanomolar potency versus; Plasmodium; DHODH and; Plasmodium; parasites were identified with good pharmacological properties. X-ray studies showed that the pyrroles bind an alternative enzyme conformation from; 1; leading to improved species selectivity versus mammalian enzymes and equivalent activity on; Plasmodium falciparum; and; Plasmodium vivax; DHODH. The best lead DSM502 (; 37; ) showed; in vivo; efficacy at similar levels of blood exposure to; 1; , although metabolic stability was reduced. Overall, the pyrrole-based DHODH inhibitors provide an attractive alternative scaffold for the development of new antimalarial compounds.