Lead optimization of aryl and aralkyl amine-based triazolopyrimidine inhibitors of plasmodium falciparum dihydroorotate dehydrogenase with antimalarial activity in mice

Ramesh Gujjar, Farah El Mazouni, Karen White, John White, Sharon Creason, David Shackleford, Xiaoyi Deng, William Charman, Ian Bathurst, Jeremy Burrows, David Floyd, David Matthews, Frederick Buckner, Susan Charman, Margaret Phillips, Pradip Rathod

Research output: Contribution to journalArticleResearchpeer-review

124 Citations (Scopus)


Malaria is one of the leading causes of severe infectious disease worldwide; yet, our ability to maintain effective therapy to combat the illness is continually challenged by the emergence of drug resistance. We previously reported identification of a new class of triazolopyrimidine-based Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors with antimalarial activity, leading to the discovery of a new lead series and novel target for drug development. Active compounds from the series contained a triazolopyrimidine ring attached to an aromatic group through a bridging nitrogen atom. Herein, we describe systematic efforts to optimize the aromatic functionality with the goal of improving potency and in vivo properties of compounds from the series. These studies led to the identification of two new substituted aniline moieties (4-SF(5)-Ph and 3,5-Di-F-4-CF(3)-Ph), which, when coupled to the triazolopyrimidine ring, showed good plasma exposure and better efficacy in the Plasmodium berghei mouse model of the disease than previously reported compounds from the series.
Original languageEnglish
Pages (from-to)3935 - 3949
Number of pages15
JournalJournal of Medicinal Chemistry
Publication statusPublished - 2011

Cite this