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

  • J Med Chem. 2025 Jan 9;68(1):590-637. doi: 10.1021/acs.jmedchem.4c02394.
Zhe Nie  1 ,  Roger Bonnert  2 ,  Jet Tsien  3 ,  Xiaoyi Deng  3 ,  Christopher Higgs  1 ,  Farah El Mazouni  3 ,  Xiaoyu Zhang  3 ,  Renzhe Li  3 ,  Nhi Ho  3 ,  Victoria Feher  1 ,  Janet Paulsen  1 ,  David M Shackleford  4 ,  Kasiram Katneni  4 ,  Gong Chen  4 ,  Alice C F Ng  4 ,  Mitchell McInerney  4 ,  Wen Wang  4 ,  Jessica Saunders  4 ,  Daniel Collins  4 ,  Dandan Yan  4 ,  Peng Li  4 ,  Michael Campbell  4 ,  Rahul Patil  4 ,  Atanu Ghoshal  5 ,  Pallab Mondal  5 ,  Abhijit Kundu  5 ,  Rajesh Chittimalla  6 ,  Muralikumar Mahadeva  6 ,  Sreekanth Kokkonda  7 ,  John White  7 ,  Rishi Das  5 ,  Partha Mukherjee  5 ,  Iñigo Angulo-Barturen  8 ,  María Belén Jiménez-Díaz  8 ,  Robert Malmstrom  1 ,  Morgan Lawrenz  1 ,  Agustina Rodriguez-Granillo  1 ,  Pradipsinh K Rathod  7 ,  Diana R Tomchick  9 ,  Michael J Palmer  2 ,  Benoît Laleu  2 ,  Tian Qin  3 ,  Susan A Charman  4 ,  Margaret A Phillips  3
Affiliations
  • 1. Schrödinger Inc., 1540 Broadway, New York, New York 10036, United States.
  • 2. MMV Medicines for Malaria Venture, ICC, Route de Pré-Bois 20, 1215 Geneva, Switzerland.
  • 3. Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States.
  • 4. Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia.
  • 5. TCGLS, Block BN, Plot 7, Salt Lake Electronics Complex, Sector V, Kolkata 700091, West Bengal, India.
  • 6. Syngene Scientific Solutions Limited, KSP 9000 Campus, Plot No. 7, Neovantage, Synergy Square 2, Kolthur Village, Shameerpet Mandal, Medchal Malkajgiri District, Hyderabad 500 078, Telangana, India.
  • 7. Department of Chemistry, University of Washington, Seattle, Washington 98195, United States.
  • 8. The Art of Discovery, Biscay Science and Technology Park, Astondo Bidea, BIC Bizkaia Bd 612, Derio, 48160 Bizkaia, Basque Country, Spain.
  • 9. Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States.
PMID: 39710971 DOI: 10.1021/acs.jmedchem.4c02394
Abstract

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.

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