The aza-analogues of 1,4-naphthoquinones are potent substrates and inhibitors of plasmodial thioredoxin and glutathione reductases and of human erythrocyte glutathione reductase

Abstract

Various aza-analogues of 1,4-naphthoquinone and menadione were prepared and tested as inhibitors and substrates of the plasmodial thioredoxin and glutathione reductases as well as the human glutathione reductase. The replacement of one to two carbons at the phenyl ring of the 1,4-naphthoquinone core by one to two nitrogen atoms led to an increased oxidant character of the molecules in accordance with both the redox potential values and the substrate efficiencies. Compared to the 1,4-naphthoquinone and menadione, the quinoline-5,8-dione 1 and both quinoxaline-5,8-diones 5 and 6 behaved as the most efficient subversive substrates of the three NADPH-dependent disulfide reductases tested. Modulation of these parameters was observed by alkylation of the aza-naphthoquinone core.

A Partial Convergence in Action of Methylene Blue and Artemisinins: Antagonism with Chloroquine, a Reversal with Verapamil, and an Insight into the Antimalarial Activity of Chloroquine

“…[35] This important precept underpins our proposal [3] that antimalarial redox-active quinones and their hydroquinone conjugates [14,36] form p complexes or associate with FAD via hydrogen bonding, and thus interfere, both physically and through modulation of redox potential, [34] with the transfer of reducing equivalents from NADPH. In this way, such compounds exert their antimalarial activity.…”

“…[13,14] Overall, artemisinins, like MB, must perturb redox balance and engender futile consumption of NADPH. NADPH consumption in yeast GR, a surrogate for parasite GR, in the presence of its substrate GSSG is enhanced by artemisinin, especially under aerobic conditions.…”

Molecular Genetics Evidence for the in Vivo Roles of the Two Major NADPH-dependent Disulfide Reductases in the Malaria Parasite

“…TrxR was discussed as a promising enzymic drug target because (i) knockout data pointed toward essentiality of the enzyme for blood stage parasites (17), (ii) detailed mechanistic and kinetic properties of PfTrxR are known (Ref. 37, and references therein), (iii) structural differences between the selenoprotein hTrxR and PfTrxR occurring at the solvent exposed C-terminal end of the proteins were considered most attractive sites for directed inhibitor development (22,37), and (iv) numerous PfTrxR inhibitors had been developed (38,39).…”

The Antimalarial Activities of Methylene Blue and the 1,4-Naphthoquinone 3-[4-(Trifluoromethyl)Benzyl]-Menadione Are Not Due to Inhibition of the Mitochondrial Electron Transport Chain

“…Even under highly reducing intracellular conditions with an estimated half-cell redox potential for NADPH around Ϫ0.34 V (48), the redox potential for atovaquone will be too low for efficient reduction by two-electron reduced GRs, which have redox potentials around Ϫ0.24 V at pH 7 (49). In contrast, the two-electron reduction potentials for methylene blue and menadione at pH 7 are ϩ0.01 V (50) and Ϫ0.23 V (51), respectively, and cyclic voltammetry measurements show that one-electron and two-electron transfer reactions are kinetically reversible (46). These properties allow a continuous reduction and oxidation under physiological conditions, which is a prerequisite for a subversive substratedriven redox cycle (Fig.…”