Antiplasmodial Activity of Nitroaromatic Compounds: Correlation with Their Reduction Potential and Inhibitory Action on Glutathione Reductase.
Fiche publication
Date publication
décembre 2019
Journal
Molecules (Basel, Switzerland)
Auteurs
Membres identifiés du Cancéropôle Est :
Dr DAVIOUD-CHARVET Elisabeth
Tous les auteurs :
Marozienė A, Lesanavičius M, Davioud-Charvet E, Aliverti A, Grellier P, Šarlauskas J, Čėnas N
Lien Pubmed
Résumé
With the aim to clarify the mechanism(s) of action of nitroaromatic compounds against the malaria parasite , we examined the single-electron reduction by ferredoxin:NADP oxidoreductase (FNR) of a series of nitrofurans and nitrobenzenes ( = 23), and their ability to inhibit glutathione reductase (GR). The reactivity of nitroaromatics in FNR-catalyzed reactions increased with their single-electron reduction midpoint potential (). Nitroaromatic compounds acted as non- or uncompetitive inhibitors towards GR with respect to NADPH and glutathione substrates. Using multiparameter regression analysis, we found that the in vitro activity of these compounds against strain FcB1 increased with their values, octanol/water distribution coefficients at pH 7.0 (log ), and their activity as GR inhibitors. Our data demonstrate that both factors, the ease of reductive activation and the inhibition of GR, 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.
Mots clés
Plasmodium falciparum, enzyme inhibition, ferredoxin:NADP+ oxidoreductase, glutathione reductase, nitroaromatics
Référence
Molecules. 2019 Dec 10;24(24):