Structure-Based\nDiscovery and Development of Highly\nPotent Dihydroorotate Dehydrogenase Inhibitors for Malaria Chemoprevention

Malaria remains a serious global health challenge, yet\ntreatment\nand control programs are threatened by drug resistance. Dihydroorotate\ndehydrogenase (DHODH) was clinically validated as a target for treatment\nand prevention of malaria through human studies with DSM265, but currently\nno drugs against this target are in clinical use. We used structure-based\ncomputational tools including free energy perturbation (FEP+) to discover\nhighly ligand efficient, potent, and selective pyrazole-based <i>Plasmodium</i> DHODH inhibitors through a scaffold hop from\na pyrrole-based series. Optimized pyrazole-based compounds were identified\nwith low nM-to-pM Plasmodium falciparum cell potency and oral activity in a humanized SCID mouse malaria\ninfection model. The lead compound DSM1465 is more potent and has\nimproved absorption, distribution, metabolism and excretion/pharmacokinetic\n(ADME/PK) properties compared to DSM265 that support the potential\nfor once-monthly chemoprevention at a low dose. This compound meets\nthe objective of identifying compounds with potential to be used for\nmonthly chemoprevention in Africa to support malaria elimination efforts.