Authors
Malaria remains a serious global health challenge, yet treatment and control programs are threatened by drugresistance. Dihydroorotate dehydrogenase (DHODH) was clinically validated as a target for treatment and prevention of malariathrough human studies with DSM265, but currently no drugs against this target are in clinical use. We used structure-basedcomputational 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 compoundswere identified with low nM-to-pM Plasmodium falciparum cell potency and oral activity in a humanized SCID mouse malariainfection model. The lead compound DSM1465 is more potent and has improved absorption, distribution, metabolism andexcretion/pharmacokinetic (ADME/PK) properties compared to DSM265 that support the potential for once-monthlychemoprevention at a low dose. This compound meets the objective of identifying compounds with potential to be used formonthly chemoprevention in Africa to support malaria elimination efforts.
