Glutathione Reductase-Catalyzed Cascade of Redox Reactions To Bioactivate Potent Antimalarial 1,4-Naphthoquinones – A New Strategy to Combat Malarial Parasites

Abstract

Our work on targeting redox equilibria of malarial parasites propagating in red blood cells has led to the selection of six 1,4-naphthoquinones, which are active at nanomolar concentrations against the human pathogen Plasmodium falciparum in culture and against Plasmodium berghei in infected mice. With respect to safety, the compounds do not trigger hemolysis or other signs of toxicity in mice. Concerning the antimalarial mode of action, we propose that the lead benzyl naphthoquinones are initially oxidized at the benzylic chain to benzoyl naphthoquinones in a heme-catalyzed reaction within the digestive acidic vesicles of the parasite. The major putative benzoyl metabolites were then found to function as redox cyclers: (i) in their oxidized form, the benzoyl metabolites are reduced by NADPH in glutathione reductase-catalyzed reactions within the cytosols of infected red blood cells; (ii) in their reduced forms, these benzoyl metabolites can convert methemoglobin, the major nutrient of the parasite, to indigestible hemoglobin. Studies on a fluorinated suicide-substrate indicate as well that the glutathione reductase-catalyzed bioactivation of naphthoquinones is essential for the observed antimalarial activity. In conclusion, the antimalarial naphthoquinones are suggested to perturb the major redox equilibria of the targeted infected red blood cells, which might be removed by macrophages. This results in development arrest and death of the malaria parasite at the trophozoite stage.

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

“…Previously, we presented the chemical design and synthesis of a novel class of compounds, the 3-[substituted-benzyl]-menadiones, that exhibit potent activities against P. falciparum blood stages in vitro and moderate activities in vivo in P. berghei-infected mice following intraperitoneal or oral administration (3). From the group of active benzylmenadione derivatives, we selected 3-[4-(trifluoromethyl)benzyl]-menadione 1c, henceforth called plasmodione (formerly also referred to as benzylnaphthoquinone 1c or benzylMD 1c [3]), as an early lead compound for further studies, such as characterization and evaluation of its antimalarial activity profile, chemical optimization, and studies on its mode of action.…”

“…From the group of active benzylmenadione derivatives, we selected 3-[4-(trifluoromethyl)benzyl]-menadione 1c, henceforth called plasmodione (formerly also referred to as benzylnaphthoquinone 1c or benzylMD 1c [3]), as an early lead compound for further studies, such as characterization and evaluation of its antimalarial activity profile, chemical optimization, and studies on its mode of action. Compared to other benzylmenadione derivatives, the plasmodione lead stands out due to its promising in vitro antiplasmodial activity, initial favorable safety profile, low cost of production, and simple synthesis route ( Fig.…”

“…Compared to other benzylmenadione derivatives, the plasmodione lead stands out due to its promising in vitro antiplasmodial activity, initial favorable safety profile, low cost of production, and simple synthesis route ( Fig. 1 shows the structure of plasmodione) (3). The synthesis of plasmodione is achieved in only one step from cheap commercially available starting materials, and its low-molecular-weight structure provides a large chemical space for optimization by derivatization (3).…”

“…1 shows the structure of plasmodione) (3). The synthesis of plasmodione is achieved in only one step from cheap commercially available starting materials, and its low-molecular-weight structure provides a large chemical space for optimization by derivatization (3). Its structure served as a starting point for development of chemical optimization strategies aimed at generating benzylmenadione derivatives with superior pharmacokinetic or pharmacodynamic properties (4)(5)(6)(7).…”

“…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.…”