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

Published in: Journal of Medicinal Chemistry

J. Med. Chem. 2025, 68, 590−637

DOI: 10.1021/acs.jmedchem.4c02394

AuthorsZhe Nie, Roger Bonnert, Jet Tsien, Xiaoyi Deng, Christopher Higgs, Farah El Mazouni, Xiaoyu Zhang,Renzhe Li, Nhi Ho, Victoria Feher, Janet Paulsen, David M. Shackleford, KasiramKatneni, Gong Chen,Alice C. F. Ng, Mitchell McInerney, Wen Wang, Jessica Saunders, Daniel Collins, Dandan Yan, Peng Li,Michael Campbell, Rahul Patil, Atanu Ghoshal[TCGLS Member], Pallab Mondal[TCGLS Member], Abhijit Kundu[TCGLS Member], Rajesh Chittimalla,Muralikumar Mahadeva, Sreekanth Kokkonda, John White, Rishi Das[TCGLS Member], Partha Mukherjee[TCGLS Member],Iñigo Angulo-Barturen, María Belén Jiménez-Díaz, Robert Malmstrom, Morgan Lawrenz,Agustina Rodriguez-Granillo, Pradipsinh K. Rathod, Diana R. Tomchick, Michael J. Palmer, Benoît Laleu,Tian Qin, Susan A. Charman,* and Margaret A. Phillips*

Abstract: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.