2. Academic Validation
  3. Tetrahydro-2-naphthyl and 2-Indanyl Triazolopyrimidines Targeting Plasmodium falciparum Dihydroorotate Dehydrogenase Display Potent and Selective Antimalarial Activity

Tetrahydro-2-naphthyl and 2-Indanyl Triazolopyrimidines Targeting Plasmodium falciparum Dihydroorotate Dehydrogenase Display Potent and Selective Antimalarial Activity

  • J Med Chem. 2016 Jun 9;59(11):5416-31. doi: 10.1021/acs.jmedchem.6b00275.
Sreekanth Kokkonda 1,  Xiaoyi Deng,  Karen L White 2,  Jose M Coteron 3,  Maria Marco 3,  Laura de Las Heras 3,  John White 1,  Farah El Mazouni,  Diana R Tomchick,  Krishne Manjalanagara 4,  Kakali Rani Rudra 4,  Gong Chen 2,  Julia Morizzi 2,  Eileen Ryan 2,  Werner Kaminsky 1,  Didier Leroy 5,  María Santos Martínez-Martínez 3,  Maria Belen Jimenez-Diaz 3,  Santiago Ferrer Bazaga 3,  Iñigo Angulo-Barturen 3,  David Waterson 5,  Jeremy N Burrows 5,  Dave Matthews 5,  Susan A Charman 2,  Margaret A Phillips,  Pradipsinh K Rathod 1
Affiliations

Affiliations

  • 1 Departments of Chemistry and Global Health, University of Washington , Seattle, Washington 98195, United States.
  • 2 Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University , Parkville, VIC 3052, Australia.
  • 3 GSK , Tres Cantos Medicines Development Campus, Severo Ochoa, Madrid 28760 Spain.
  • 4 Syngene International Ltd. , Bangalore 560 099, India.
  • 5 Medicines for Malaria Venture , 1215 Geneva, Switzerland.
PMID: 27127993 DOI: 10.1021/acs.jmedchem.6b00275
Abstract

Malaria persists as one of the most devastating global infectious diseases. The pyrimidine biosynthetic enzyme Dihydroorotate Dehydrogenase (DHODH) has been identified as a new malaria drug target, and a triazolopyrimidine-based DHODH inhibitor 1 (DSM265) is in clinical development. We sought to identify compounds with higher potency against Plasmodium DHODH while showing greater selectivity toward animal DHODHs. Herein we describe a series of novel triazolopyrimidines wherein the p-SF5-aniline was replaced with substituted 1,2,3,4-tetrahydro-2-naphthyl or 2-indanyl amines. These compounds showed strong species selectivity, and several highly potent tetrahydro-2-naphthyl derivatives were identified. Compounds with halogen substitutions displayed sustained plasma levels after oral dosing in rodents leading to efficacy in the P. falciparum SCID mouse malaria model. These data suggest that tetrahydro-2-naphthyl derivatives have the potential to be efficacious for the treatment of malaria, but due to higher metabolic clearance than 1, they most likely would need to be part of a multidose regimen.

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