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

Ramesh Gujjar, Alka Marwaha, Farah El Mazouni, John White, Karen Louise White, Sharon Creason, David Shackleford, Jeffrey Baldwin, William Neil Charman, Frederick S Buckner, Susan Ann Charman, Pradip Rathod, Margaret Phillips

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175 Citations (Scopus)

Abstract

Plasmodium falciparum causes 1-2 million deaths annually. Yet current drug therapies are compromised be resistance. We previously described potent and selective triazolopyrimidine-based inhibitors of P. falciparum dihydroorate dehydrogenase 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 napthyl (DSM1) or anthracenyl (DSM2), plama exposure was reduced upon repeated dosing. Phenyl-substituted traizolopyrimidines 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.
Original languageEnglish
Pages (from-to)1864 - 1872
Number of pages9
JournalJournal of Medicinal Chemistry
Volume52
Issue number7
DOIs
Publication statusPublished - 2009

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