Medicinal Chemistry Case History: Discovery of the Dihydroorate Dehydrogenase Inhibitor DSM265 as an Antimalarial Drug Candidate

Half of the globe remains at risk for malaria, yet drug resistance threatens current treatments. DSM265 was discovered through a target-based screen and subsequent structure-guided lead optimization, as a novel triazolopyrimidine-based inhibitor of Plasmodium dihydroorotate dehydrogenase (DHODH). DSM265 is the first antimalarial targeting DHODH and, due to its novel mechanism, is expected to function against Plasmodium species resistant to current chemotherapies. Key DSM265 characteristics include blood- and liver-stage activity, parasite selectivity, and a long human half-life, supporting its development as either a single dose treatment or once weekly prophylactic, in combination with a suitable partner to help prevent resistance.