Tetraoxane-pyrimidine nitrile hybrids as dual stage antimalarials

Rudi Oliveira, Rita C. Guedes, Patrícia Meireles, Inês S. Albuquerque, Lídia M. Gonçalves, Elisabete Pires, Maria do Rosário Bronze, Jiri Gut, Philip J. Rosenthal, Miguel Prudêncio, Rui Moreira, Paul M. O'Neill, Francisca Lopes

Research output: Contribution to journalArticlepeer-review

39 Citations (Scopus)


The use of artemisinin or other endoperoxides in combination with other drugs is a strategy to prevent development of resistant strains of Plasmodium parasites. Our previous work demonstrated that hybrid compounds, comprising endoperoxides and vinyl sulfones, were capable of high activity profiles comparable to artemisinin and chloroquine while acting through two distinct mechanisms of action: oxidative stress and falcipain inhibition. In this study, we adapted this approach to a novel class of falcipain inhibitors: peptidomimetic pyrimidine nitriles. Pyrimidine tetraoxane hybrids displayed potent nanomolar activity against three strains of Plasmodium falciparum and falcipain-2, combined with low cytotoxicity. In vivo, a decrease in parasitemia and an increase in survival of mice infected with Plasmodium berghei was observed when compared to control. All tested compounds combined good blood stage activity with significant effects on liver stage parasitemia, a most welcome feature for any new class of antimalarial drug.

Original languageEnglish
Pages (from-to)4916-4923
Number of pages8
JournalJournal Of Medicinal Chemistry
Issue number11
Publication statusPublished - 12 Jun 2014


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