Tetraoxane鈥揚yrimidine Nitrile Hybrids as Dual Stage Antimalarials
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- 作者：Rudi Oliveira ; Rita C. Guedes ; Patr铆cia Meireles ; In锚s S. Albuquerque ; L铆dia M. Gon莽alves ; Elisabete Pires ; Maria Ros谩rio Bronze ; Jiri Gut ; Philip J. Rosenthal ; Miguel Prud锚ncio ; Rui Moreira ; Paul M. O鈥橬eill ; Francisca Lopes
- 刊名：Journal of Medicinal Chemistry
- 出版年：2014
- 出版时间：June 12, 2014
- 年：2014
- 卷：57
- 期：11
- 页码：4916-4923
- 全文大小：406K
- 年卷期：v.57,no.11(June 12, 2014)
- ISSN：1520-4804
文摘
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.