Antimalarial NADPH-Consuming Redox-Cyclers As Superior Glucose-6-Phosphate Dehydrogenase Deficiency Copycats

Abstract

Aims: Early phagocytosis of glucose-6-phosphate dehydrogenase (G6PD)-deficient erythrocytes parasitized by Plasmodium falciparum were shown to protect G6PD-deficient populations from severe malaria. Here, we investigated the mechanism of a novel antimalarial series, namely 3-[substituted-benzyl]-menadiones, to understand whether these NADPH-consuming redox-cyclers, which induce oxidative stress, mimic the natural protection of G6PD deficiency. Results: We demonstrated that the key benzoylmenadione metabolite of the lead compound acts as an efficient redox-cycler in NADPH-dependent methaemoglobin reduction, leading to the continuous formation of reactive oxygen species, ferrylhaemoglobin, and subsequent haemichrome precipitation. Structure–activity relationships evidenced that both drug metabolites and haemoglobin catabolites contribute to potentiate drug effects and inhibit parasite development. Disruption of redox homeostasis by the lead benzylmenadione was specifically induced in Plasmodium falciparum parasitized erythrocytes and not in non-infected cells, and was visualized via changes in the glutathione redox potential of living parasite cytosols. Furthermore, the redox-cycler shows additive and synergistic effects in combination with compounds affecting the NADPH flux in vivo. Innovation: The lead benzylmenadione 1c is the first example of a novel redox-active agent that mimics the behavior of a falciparum parasite developing inside a G6PD-deficient red blood cell (RBC) giving rise to malaria protection, and it exerts specific additive effects that are inhibitory to parasite development, without harm for non-infected G6PD-sufficient or -deficient RBCs. Conclusion: This strategy offers an innovative perspective for the development of future antimalarial drugs for G6PD-sufficient and -deficient populations. Antioxid. Redox Signal. 22, 1337–1351.

The Redox Cycler Plasmodione Is a Fast-Acting Antimalarial Lead Compound with Pronounced Activity against Sexual and Early Asexual Blood-Stage Parasites

“…We also showed that plasmodione specifically induces its toxic effects in parasitized erythrocytes without harming noninfected G6PD-sufficient or -deficient erythrocytes (11). The other drug activities referred to include the generation of drug metabolites acting on other targets, such as glutathione reductasecatalyzed redox cycling, methemoglobin reduction, iron(III) complexation, and inhibition of ␤-hematin formation, which are suggested to play a significant role in killing the parasite (11). It is noteworthy that in contrast to the structurally related antimalarial 1,4-naphthoquinone atovaquone, the lead benzylmenadione does not act as an inhibitor of the parasite's mitochondrial electron transport chain (8).…”

“…This deficiency stems from genetic mutations in the G6PD gene (12)(13)(14) resulting in reduced antioxidative capacities of erythrocytes and an early removal of Plasmodium-infected erythrocytes from the circulation. We recently demonstrated that among other activities, plasmodione mimics the natural protection of G6PD deficiency, marked by oxidative damage of P. falciparum-infected erythrocytes and their enhanced phagocytosis upon drug treatment (11). We also showed that plasmodione specifically induces its toxic effects in parasitized erythrocytes without harming noninfected G6PD-sufficient or -deficient erythrocytes (11).…”

“…Studies on the mode of action have suggested that plasmodione, like other benzylmenadione derivatives, acts as a redox cycler, thereby disrupting the redox homeostasis of the parasitized erythrocyte (3,(8)(9)(10)(11). Interfering with the parasite's redox balance is a largely unexploited but highly effective strategy to restrict parasite development.…”

“…We recently demonstrated that among other activities, plasmodione mimics the natural protection of G6PD deficiency, marked by oxidative damage of P. falciparum-infected erythrocytes and their enhanced phagocytosis upon drug treatment (11). We also showed that plasmodione specifically induces its toxic effects in parasitized erythrocytes without harming noninfected G6PD-sufficient or -deficient erythrocytes (11). The other drug activities referred to include the generation of drug metabolites acting on other targets, such as glutathione reductasecatalyzed redox cycling, methemoglobin reduction, iron(III) complexation, and inhibition of ␤-hematin formation, which are suggested to play a significant role in killing the parasite (11).…”

Prevalence of glucose-6-phosphate dehydrogenase (G6PD) deficiency in malaria endemic region of Iran (Sistan and Baluchestan Province): Epidemiological profile and trends over time

“…To achieve the radical treatment and elimination of Plasmodium parasites, especially Plasmodium falciparum, antimalarial drugs such as primaquine are required. These drugs act as oxidant and may lead to haemolysis in people with G6PD deficiency [6,19]. Therefore, knowledge about the prevalence of G6PD deficiency and other triggers of haemolysis for eradication of malaria is important.…”