Antiplasmodial Activity of Nitroaromatic and Quinoidal Compounds: Redox Potential vs Inhibition of Erythrocyte Glutathione Reductase

Prooxidant nitroaromatic and quinoidal compounds possess antimalarial activity, which might be attributed either to their formation of reactive oxygen species or to their inhibition of antioxidant enzyme glutathione reductase (GR, EC 1.6.4.2). We have examined the activity in vitro against Plasmodium falciparum of 24 prooxidant compounds of different structure (nitrobenzenes, nitrofurans, quinones, 1,1′-dibenzyl-4,4′-bipyridinium, and methylene blue), which possess a broad range of single-electron reduction potentials (E17) and erythrocyte glutathione reductase inhibition constants (Ki(GR)). For a series of homologous derivatives of 2-(5′-nitrofurylvinyl)quinoline-4-carbonic acid, the relationship between compound Ki(GR) and concentration causing 50% parasite growth inhibition (IC50) was absent. For all the compounds examined in this study, the dependence of IC50 on their Ki(GR) was insignificant. In contrast, IC50 decreased with an increase in E17 and positive electrostatic charge of aromatic part of molecule (Z): log IC50 (μM) = −(0.9846 ± 0.3525) − (7.2850 ± 1.2340) E17 (V) − (1.1034 ± 0.1832) Z (r2 = 0.8015). The redox cycling activity of nitroaromatic and quinoidal compounds in ferredoxin:NADP+ reductase-catalyzed reaction and the rate of oxyhemoglobin oxidation in lysed erythrocytes increased with an increase in their E17 value. Our findings imply that the antiplasmodial activity of nitroaromatic and quinoidal compounds is mainly influenced by their ability to form reactive oxygen species, and much less significantly by the GR inhibition.