Identification of a metabolically stable triazolopyrimidine-based dihydroorotate dehydrogenase inhibitor with antimalarial activity in mice

  • J Med Chem. 2009 Apr 9;52(7):1864-72. doi: 10.1021/jm801343r.
Ramesh Gujjar  1 ,  Alka Marwaha ,  Farah El Mazouni ,  John White ,  Karen L White ,  Sharon Creason ,  David M Shackleford ,  Jeffrey Baldwin ,  William N Charman ,  Frederick S Buckner ,  Susan Charman ,  Pradipsinh K Rathod ,  Margaret A Phillips
Affiliations
  • 1. Department of Chemistry and Global Health and Department of Medicine, University of Washington, Seattle, Washington 98195, USA.
PMID: 19296651 DOI: 10.1021/jm801343r
Abstract

Plasmodium falciparum causes 1-2 million deaths annually. Yet current drug therapies are compromised by resistance. We previously described potent and selective triazolopyrimidine-based inhibitors of P. falciparum Dihydroorotate Dehydrogenase (PfDHODH) that inhibited Parasite growth in vitro; however, they showed no activity in vivo. Here we show that lack of efficacy against P. berghei in mice resulted from a combination of poor plasma exposure and reduced potency against P. berghei DHODH. For compounds containing naphthyl (DSM1) or anthracenyl (DSM2), plasma exposure was reduced upon repeated dosing. Phenyl-substituted triazolopyrimidines were synthesized leading to identification of analogs with low predicted metabolism in human liver microsomes and which showed prolonged exposure in mice. Compound 21 (DSM74), containing p-trifluoromethylphenyl, suppressed growth of P. berghei in mice after oral administration. This study provides the first proof of concept that DHODH inhibitors can suppress Plasmodium growth in vivo, validating DHODH as a new target for antimalarial chemotherapy.

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