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

Ehrhardt, Katharina; Davioud‐Charvet, Elisabeth; Ke, Hangjun; Vaidya, Akhil B.; Lanzer, Michael; Deponte, Marcel

doi:10.1128/aac.02248-12

Cited by 39 publications

(51 citation statements)

References 56 publications

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“…3a, plot I). The potent activity of plasmodione against ring stages is supported by previous morphological studies, which revealed that ring-stage parasites develop a characteristic pyknotic morphology upon drug treatment (3,8).…”

Section: Resultssupporting

confidence: 63%

“…In vitro antiplasmodial activity is expressed as the 50% inhibitory concentration (IC 50 ) or 90% inhibitory concentration (IC 90 ) for inhibition of parasite development. Activities of plasmodione and chloroquine against the P. falciparum 3D7 and Dd2 strains (as presented in Table 1 and in Table S1 in the supplemental material) were determined in laboratory A by using the SYBR green I assay as described before (8,29). Briefly, synchronous ring-stage parasites were incubated for 72 h in the presence of decreasing drug concentrations in microtiter plates (final parasitemia, 0.5%; final hematocrit, 1.5%).…”

Section: Methodsmentioning

confidence: 99%

“…Cultures were maintained under the following controlled atmospheric conditions: for laboratory A, an incubator with a fixed atmosphere of 5% O 2 , 3% CO 2 , 92% N 2 , and 95% humidity at 37°C (8); for continuous parasite cultures in laboratory B, a fixed atmosphere of 6% O 2 , 3% CO 2 , and 91% N 2 ; for short-term experiments in laboratory B, a candle jar with an atmosphere of approximately 17% O 2 , 3% CO 2 , and 80% N 2 at 37°C; for laboratory C, an incubator with a fixed atmosphere of 10% O 2 , 5% CO 2 , and 85% N 2 at 37°C and a humidity of 95%; and for laboratory D, a fixed atmosphere of 5% O 2 , 5% CO 2 , and 90% N 2 . Synchronization of cultures over a large time window (0 to 20 h postinvasion [p.i.])…”

Section: Methodsmentioning

confidence: 99%

“…The other drug activities referred to include the generation of drug metabolites acting on other targets, such as glutathione reductasecatalyzed redox cycling, methemoglobin reduction, iron(III) complexation, and inhibition of ␤-hematin formation, which are suggested to play a significant role in killing the parasite (11). It is noteworthy that in contrast to the structurally related antimalarial 1,4-naphthoquinone atovaquone, the lead benzylmenadione does not act as an inhibitor of the parasite's mitochondrial electron transport chain (8).…”

mentioning

confidence: 99%

“…Studies on the mode of action have suggested that plasmodione, like other benzylmenadione derivatives, acts as a redox cycler, thereby disrupting the redox homeostasis of the parasitized erythrocyte (3,(8)(9)(10)(11). Interfering with the parasite's redox balance is a largely unexploited but highly effective strategy to restrict parasite development.…”

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confidence: 99%

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The Redox Cycler Plasmodione Is a Fast-Acting Antimalarial Lead Compound with Pronounced Activity against Sexual and Early Asexual Blood-Stage Parasites

Ehrhardt

Deregnaucourt

Goetz

et al. 2016

Antimicrob Agents Chemother

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Previously, we presented the chemical design of a promising series of antimalarial agents, 3-[substituted-benzyl]-menadiones, with potent in vitro and in vivo activities. Ongoing studies on the mode of action of antimalarial 3-[substituted-benzyl]-menadiones revealed that these agents disturb the redox balance of the parasitized erythrocyte by acting as redox cyclers-a strategy that is broadly recognized for the development of new antimalarial agents. Here we report a detailed parasitological characterization of the in vitro activity profile of the lead compound 3-[4-(trifluoromethyl)benzyl]-menadione 1c (henceforth called plasmodione) against intraerythrocytic stages of the human malaria parasite Plasmodium falciparum. We show that plasmodione acts rapidly against asexual blood stages, thereby disrupting the clinically relevant intraerythrocytic life cycle of the parasite, and furthermore has potent activity against early gametocytes. The lead's antiplasmodial activity was unaffected by the most common mechanisms of resistance to clinically used antimalarials. Moreover, plasmodione has a low potential to induce drug resistance and a high killing speed, as observed by culturing parasites under continuous drug pressure. Drug interactions with licensed antimalarial drugs were also established using the fixed-ratio isobologram method. Initial toxicological profiling suggests that plasmodione is a safe agent for possible human use. Our studies identify plasmodione as a promising antimalarial lead compound and strongly support the future development of redox-active benzylmenadiones as antimalarial agents.M alaria remains one of the most severe infectious diseases that disproportionately affects the public health and economic welfare of the world's poorest communities. The causative agents of malaria are protozoan parasites of the genus Plasmodium. Among the five Plasmodium species that can cause malaria in humans (Plasmodium falciparum, P. vivax, P. ovale, P. malariae, and P. knowlesi), P. falciparum is the most virulent and is responsible for severe clinical outcomes and most of the deaths associated with malaria. Until the development of an effective vaccine, chemotherapy remains a major frontline strategy for the control and possible future elimination of malaria. The emergence and rapid spread of drug-resistant parasites undermine efforts at reducing the global disease burden and emphasize the need for drugs with novel chemical entities that exploit new molecular targets while overcoming established drug resistance mechanisms. Ideally, such drugs should quickly kill the pathogenic asexual blood stages of P. falciparum and, in addition, be effective against other developmental stages, in particular the sexual stages that transmit the infection from the human to the mosquito host (1, 2).Previously, we presented the chemical design and synthesis of a novel class of compounds, the 3-[substituted-benzyl]-menadiones, that exhibit potent activities against P. falciparum blood stages in vitro and moderate activities in v...

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Section: Resultssupporting

confidence: 63%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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The Redox Cycler Plasmodione Is a Fast-Acting Antimalarial Lead Compound with Pronounced Activity against Sexual and Early Asexual Blood-Stage Parasites

Ehrhardt

Deregnaucourt

Goetz

et al. 2016

Antimicrob Agents Chemother

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Redox Polypharmacology as an Emerging Strategy to Combat Malarial Parasites

et al. 2016

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3-Benzylmenadiones are potent antimalarial agents that are thought to act through their 3-benzoylmenadione metabolites as redox cyclers of two essential targets: the NADPH-dependent glutathione reductases (GRs) of Plasmodium-parasitized erythrocytes and methemoglobin. Their physicochemical properties were characterized in a coupled assay using both targets and modeled with QSPR predictive tools built in house. The substitution pattern of the west/east aromatic parts that controls the oxidant character of the electrophore was highlighted and accurately predicted by QSPR models. The effects centered on the benz(o)yl chain, induced by drug bioactivation, markedly influenced the oxidant character of the reduced species through a large anodic shift of the redox potentials that correlated with the redox cycling of both targets in the coupled assay. Our approach demonstrates that the antimalarial activity of 3-benz(o)ylmenadiones results from a subtle interplay between bioactivation, fine-tuned redox properties, and interactions with crucial targets of P. falciparum. Plasmodione and its analogues give emphasis to redox polypharmacology, which constitutes an innovative approach to antimalarial therapy.

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A Platform of Regioselective Methodologies to Access Polysubstituted 2‐Methyl‐1,4‐naphthoquinone Derivatives: Scope and Limitations

Rodo¹,

Feng²,

Jida³

et al. 2016

Eur J Org Chem

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A platform of synthetic methodologies has been established to access a focused library of polysubstituted 3‐benzylmenadione derivatives functionalized on the aromatic ring of the naphthoquinone core. Two main routes were explored: 1) The naphthol route, starting from either an α‐tetralone or a propiophenone, and 2) the regioselective Diels–Alder reaction, starting from various dienes and two 2‐bromo‐5(or 6)‐methyl‐1,4‐benzoquinones. 6‐Substituted 2‐methylnaphthols were synthesized by using a xanthate‐mediated free‐radical addition/cyclization sequence for the construction of the 6‐substituted menadione subunit. Furthermore, an efficient and simple new pathway that allows the formation of 6‐ or 7‐substituted 3‐(substituted‐benzyl)menadione regioisomers from a common commercial scaffold has also been developed by the naphthol route, advantageous with regard to step economy. Our synthetic methodologies exemplified by 34 compounds have allowed structure–activity relationships to be deduced for use as the basis for the development of new antimalarial redox‐active polysubstituted benzylmenadione derivatives.

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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

Cited by 39 publications

References 56 publications

The Redox Cycler Plasmodione Is a Fast-Acting Antimalarial Lead Compound with Pronounced Activity against Sexual and Early Asexual Blood-Stage Parasites

The Redox Cycler Plasmodione Is a Fast-Acting Antimalarial Lead Compound with Pronounced Activity against Sexual and Early Asexual Blood-Stage Parasites

Redox Polypharmacology as an Emerging Strategy to Combat Malarial Parasites

A Platform of Regioselective Methodologies to Access Polysubstituted 2‐Methyl‐1,4‐naphthoquinone Derivatives: Scope and Limitations

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