Abstract
With the aim to clarify the mechanism(s) of action of nitroaromatic compounds against the malaria parasite Plasmodium falciparum, we examined the single-electron reduction by P. falciparum ferredoxin:NADP+ oxidoreductase (PfFNR) of a series of nitrofurans and nitrobenzenes (n = 23), and their ability to inhibit P. falciparum glutathione reductase (PfGR). The reactivity of nitroaromatics in PfFNR-catalyzed reactions increased with their single-electron reduction midpoint potential (E17). Nitroaromatic compounds acted as non- or uncompetitive inhibitors towards PfGR with respect to NADPH and glutathione substrates. Using multiparameter regression analysis, we found that the in vitro activity of these compounds against P. falciparum strain FcB1 increased with their E17 values, octanol/water distribution coefficients at pH 7.0 (log D), and their activity as PfGR inhibitors. Our data demonstrate that both factors, the ease of reductive activation and the inhibition of PfGR, are important in the antiplasmodial in vitro activity of nitroaromatics. To the best of our knowledge, this is the first quantitative demonstration of this kind of relationship. No correlation between antiplasmodial activity and ability to inhibit human erythrocyte GR was detected in tested nitroaromatics. Our data suggest that the efficacy of prooxidant antiparasitic agents may be achieved through their combined action, namely inhibition of antioxidant NADPH:disulfide reductases, and the rapid reduction by single-electron transferring dehydrogenases-electrontransferases.
Highlights
The emergence of the resistance of the malaria parasite Plasmodium falciparum to available drugs has resulted in the demand for new antimalarial agents and in a better understanding of their mechanisms of action
Extending our previous studies [19,30], here we demonstrate that the in vitro antiplasmodial activity of nitroaromatic compounds partly correlates with their efficacy as P. falciparum glutathione reductase (Pf GR) inhibitors, and partly with their reactivity with single-electron transferring P. falciparum ferredoxin:NADP+ oxidoreductase (Pf FNR)
The toxicity of nitroaromatic compounds against mammalian cells and bacteria often increases with their single-electron reduction midpoint potential
Summary
The emergence of the resistance of the malaria parasite Plasmodium falciparum to available drugs (e.g., chloroquine or artemisinin [1]) has resulted in the demand for new antimalarial agents and in a better understanding of their mechanisms of action. In addition to a number of nitroheterocyclic drugs such as nifurtimox and benznidazole that have been used against Chagas disease and sleeping sickness since the 1970s, a new 5-nitroimidazole derivative, fexinidazole, has recently been approved for a treatment against sleeping sickness [3]. The therapeutic action of ArNO2 is attributed to single-electron reduction into their anion radicals (ArNO2 − ), which in turn undergo redox cycling with the formation of ROS, or to their two/four-electron reduction into hydroxylamines (ArNHOH), able to modify DNA [4,5,6].
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