1,4-Naphthoquinones and Other NADPH-Dependent Glutathione Reductase- Catalyzed Redox Cyclers as Antimalarial Agents

Abstract

The homodimeric flavoenzyme glutathione reductase catalyzes NADPH-dependent glutathione disulfide reduction. This reaction is important for keeping the redox homeostasis in human cells and in the human pathogen Plasmodium falciparum. Different types of NADPH-dependent disulfide reductase inhibitors were designed in various chemical series to evaluate the impact of each inhibition mode on the propagation of the parasites. Against malaria parasites in cultures the most potent and specific effects were observed for redox-active agents acting as subversive substrates for both glutathione reductases of the Plasmodium-infected red blood cells. In their oxidized form, these redox-active compounds are reduced by NADPH-dependent flavoenzyme-catalyzed reactions in the cytosol of infected erythrocytes. In their reduced forms, these compounds can reduce molecular oxygen to reactive oxygen species, or reduce oxidants like methemoglobin, the major nutrient of the parasite, to indigestible hemoglobin. Furthermore, studies on a fluorinated suicide-substrate of the human glutathione reductase indicate that the glutathione reductase-catalyzed bioactivation of 3-benzylnaphthoquinones to the corresponding reduced 3-benzoyl metabolites is essential for the observed antimalarial activity. In conclusion, the antimalarial lead naphthoquinones are suggested to perturb the major redox equilibria of the targeted cells. These effects result in development arrest of the parasite and contribute to the removal of the parasitized erythrocytes by macrophages.

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

“…A far less prevalent GR deficiency or drug-induced GR inhibition may also protect from malaria due to an enhanced phagocytosis of ring-stage parasites (55). Redox-active compounds such as dapsone and primaquine can cause clinical cases of methemoglobinemia and hemolytic anemia in G6PDH-deficient patients, and the evaluation of the hemolytic risk is an essential requirement at the lead optimization stage in any antimalarial drug discovery project (57). Among the arsenal of antimalarial drugs, methylene blue proved to be safe and effective in the treatment of uncomplicated falciparum malaria when combined with other antimalarials (19).…”

Effects of a novel β–lapachone derivative on Trypanosoma cruzi : Parasite death involving apoptosis, autophagy and necrosis

“…Bernardino et al., 2006, Salas et al., 2008, Souza-Neta et al., 2014). Natural plant-derived quinones and their derivatives may exert multifactorial effects upon distinct targets on antiparasitic chemotherapy (Pinto and Castro, 2009, Salas et al., 2008, Belorgey et al., 2013). Naphtoquinones such as β–lapachone are natural products isolated from different higher plant families and shown to present antimalarial (Carvalho et al., 1988, De Andrade-Neto et al., 2004, Pérez-Sacau et al., 2005), giardicidal (Corrêa et al., 2009), leishmanicidal (Guimarães et al., 2013) and trypanocidal activity against T. brucei (De Pahn et al., 1988) and Trypanosoma cruzi (Boveris et al., 1978, Docampo et al., 1978, Goijman and Stoppani, 1985, Pinto et al., 1997, Pinto et al., 2000, Menna-Barreto et al., 2005, Menna-Barreto et al., 2007, Menna-Barreto et al., 2009a, 2014).…”

Unusual <i>O</i>-Alkylation of 2-Hydroxy-1,4-naphthoquinone Utilizing Alkoxymethyl Chlorides

“…The product ratio of 3a increased in accordance with the use of a larger amount of base and MOMCl, although excess use of these reagents caused a decrease in the 3a yield (Table 1, entries [3][4][5]. Under the slight basic conditions, namely, the reaction using excess amount of base over MOMCl resulted in a great decrease of 3a (Table 1, entry 6).…”

“…[1][2][3][4][5][6][7] Recently, our research interests have focused on the total synthesis of naturally occurring naphthoquinones, such as rinacanthin A, 8) dehydroiso-β-lapachone 9) and lantalucratins 10) having biological activities including anti-tumor activity, in order to confirm the chemical structure and determine the absolute configuration. In the course of our synthetic study, a key intermediate (I) was prepared from 1,4-dimethoxynaphthalene, which is relatively expensive as a commercial source, by the introduction of a hydroxyl group using directed ortho lithiation-substitution reaction 11) and the following hydroxyl protection by methoxymethyl group (Chart 1).…”