Tetraoxane–Pyrimidine Nitrile Hybrids as Dual Stage Antimalarials

Abstract

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.

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“…Similarly, peptidomimetic drugs are also being designed against HERES simplex viruses (HSV [81][82] .…”

Exploring the 3-piperidin-4-yl-1H-indole scaffold as a novel antimalarial chemotype

“…The strategies currently used for the development of novel antimalarial drugs include many approaches such as: the discovery of new active molecules from natural sources [16][17][18][19][20][21][22][23], repurposing of commercially available drugs, the development of hybrid compounds [24], and rational drug design with chemical modifications of existing antimalarials and hits [25][26][27], amongst others. Also, a great number of drug discovery and development programs from both public and private institutions, and publicprivate partnerships, using phenotypic screening with sensitive and resistant strains of P. falciparum have been pursued in the past recent years.…”

Inherent Flexibility vis‐à‐vis Structural Rigidity in Chemically Stable Antimalarial Dispiro N‐Sulfonylpiperidine Tetraoxanes

“…Paul M O'Niell et al, have demonstrated that tetraoxanes with vinyl sulfones acts as dual stage inhibitor and show activity comparable to artemisinin and chloroquine . They have also shown that hybrids combining tetraoxanes with the pyrimidine nitriles can affect the liver stage parasitema with significant blood stage activity …”