2. Academic Validation
  3. Lead Optimization of a Pyrrole-Based Dihydroorotate Dehydrogenase Inhibitor Series for the Treatment of Malaria

Lead Optimization of a Pyrrole-Based Dihydroorotate Dehydrogenase Inhibitor Series for the Treatment of Malaria

  • J Med Chem. 2020 May 14;63(9):4929-4956. doi: 10.1021/acs.jmedchem.0c00311.
Sreekanth Kokkonda 1,  Xiaoyi Deng 2,  Karen L White 3,  Farah El Mazouni 2,  John White 1,  David M Shackleford 3,  Kasiram Katneni 3,  Francis C K Chiu 3,  Helena Barker 3,  Jenna McLaren 3,  Elly Crighton 3,  Gong Chen 3,  Inigo Angulo-Barturen 4,  Maria Belen Jimenez-Diaz 4,  Santiago Ferrer 4,  Leticia Huertas-Valentin 4,  Maria Santos Martinez-Martinez 4,  Maria Jose Lafuente-Monasterio 4,  Rajesh Chittimalla 5,  Shatrughan P Shahi 5,  Sergio Wittlin 6 7,  David Waterson 8,  Jeremy N Burrows 8,  Dave Matthews 8,  Diana Tomchick 9,  Pradipsinh K Rathod 1,  Michael J Palmer 8,  Susan A Charman 3,  Margaret A Phillips 2
Affiliations

Affiliations

  • 1 Departments of Chemistry and Global Health, University of Washington, Seattle, Washington 98195, United States.
  • 2 Departments of Biochemistry, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd, Dallas, Texas 75390-9135, United States.
  • 3 Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
  • 4 GSK, Tres Cantos Medicines Development Campus, Severo Ochoa, Madrid 28760, Spain.
  • 5 Syngene International Ltd, Bangalore 560 099, India.
  • 6 Swiss Tropical and Public Health Institute, Socinstrasse 57, 4002 Basel, Switzerland.
  • 7 University of Basel, 4002 Basel, Switzerland.
  • 8 Medicines for Malaria Venture, 1215 Geneva, Switzerland.
  • 9 Department of Biophysics, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd, Dallas, Texas 75390-9135, United States.
PMID: 32248693 DOI: 10.1021/acs.jmedchem.0c00311
Abstract

Malaria puts at risk nearly half the world's population and causes high mortality in sub-Saharan Africa, while drug resistance threatens current therapies. The pyrimidine biosynthetic enzyme Dihydroorotate Dehydrogenase (DHODH) is a validated target for malaria treatment based on our finding that triazolopyrimidine DSM265 (1) showed efficacy in clinical studies. Herein, we describe optimization of a pyrrole-based series identified using a target-based DHODH screen. Compounds with nanomolar potency versus Plasmodium DHODH and Plasmodium parasites were identified with good pharmacological properties. X-ray studies showed that the pyrroles bind an alternative Enzyme conformation from 1 leading to improved species selectivity versus mammalian enzymes and equivalent activity on Plasmodium falciparum and Plasmodium vivax DHODH. The best lead DSM502 (37) showed in vivo efficacy at similar levels of blood exposure to 1, although metabolic stability was reduced. Overall, the pyrrole-based DHODH inhibitors provide an attractive alternative scaffold for the development of new antimalarial compounds.

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