Title Antiplasmodial activity of nitroaromatic compounds: correlation with their reduction potential and inhibitory action on Plasmodium falciparum glutathione reductase /
Authors Marozienė, Audronė ; Lesanavičius, Mindaugas ; Davioud-Charvet, Elisabeth ; Aliverti, Alessandro ; Grellier, Philippe ; Šarlauskas, Jonas ; Čėnas, Narimantas
DOI 10.3390/molecules24244509
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Is Part of Molecules.. Basel : MDPI. 2019, vol. 24, no. 24, art. no. 4509, p. [1-15].. ISSN 1420-3049
Keywords [eng] nitroaromatics ; Plasmodium falciparum ; ferredoxin:NADP+oxidoreductase ; glutathionereductase ; enzyme inhibition
Abstract [eng] With the aim to clarify the mechanism(s) of action of nitroaromatic compounds against themalaria parasitePlasmodium falciparum, we examined the single-electron reduction byP. falciparumferredoxin:NADP+oxidoreductase (PfFNR) of a series of nitrofurans and nitrobenzenes (n=23),and their ability to inhibitP. falciparumglutathione reductase (PfGR). The reactivity of nitroaromaticsinPfFNR-catalyzed reactions increased with their single-electron reduction midpoint potential (E17).Nitroaromatic compounds acted as non- or uncompetitive inhibitors towardsPfGR with respect toNADPH and glutathione substrates. Using multiparameter regression analysis, we found that thein vitroactivity of these compounds againstP. falciparumstrain FcB1 increased with theirE17values,octanol/water distribution coefficients at pH 7.0 (logD), and their activity asPfGR inhibitors. Our datademonstrate that both factors, the ease of reductive activation and the inhibition ofPfGR, are importantin the antiplasmodialin vitroactivity of nitroaromatics. To the best of our knowledge, this is thefirst quantitative demonstration of this kind of relationship. No correlation between antiplasmodialactivity and ability to inhibit human erythrocyte GR was detected in tested nitroaromatics. Our datasuggest that the efficacy of prooxidant antiparasitic agents may be achieved through their combinedaction, namely inhibition of antioxidant NADPH:disulfide reductases, and the rapid reduction bysingle-electron transferring dehydrogenases-electrontransferases.
Published Basel : MDPI
Type Journal article
Language English
Publication date 2019