Structure-Based Discovery and Development of Highly Potent Dihydroorotate Dehydrogenase Inhibitors for Malaria Chemoprevention

Malaria remains a serious global health challenge, yet
treatment
and control programs are threatened by drug resistance. Dihydroorotate
dehydrogenase (DHODH) was clinically validated as a target for treatment
and prevention of malaria through human studies with DSM265, but currently
no drugs against this target are in clinical use. We used structure-based
computational tools including free energy perturbation (FEP+) to discover
highly ligand efficient, potent, and selective pyrazole-based Plasmodium DHODH inhibitors through a scaffold hop from
a pyrrole-based series. Optimized pyrazole-based compounds were identified
with low nM-to-pM Plasmodium falciparum cell potency and oral activity in a humanized SCID mouse malaria
infection model. The lead compound DSM1465 is more potent and has
improved absorption, distribution, metabolism and excretion/pharmacokinetic
(ADME/PK) properties compared to DSM265 that support the potential
for once-monthly chemoprevention at a low dose. This compound meets
the objective of identifying compounds with potential to be used for
monthly chemoprevention in Africa to support malaria elimination efforts.