Electrochemical Properties of Substituted 2‐Methyl‐1,4‐Naphthoquinones: Redox Behavior Predictions

Elhabiri, Mourad; Sidorov, Pavel; Cesar‐Rodo, Elena; Marcou, Gilles; Lanfranchi, Don Antoine; Davioud‐Charvet, Elisabeth; Horvath, Dragos; Varnek, Alexandre

doi:10.1002/chem.201403703

Cited by 38 publications

(33 citation statements)

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“…In this section, we describe the electrochemical properties of the 3‐benz(o)ylmenadiones to evaluate the influence of the benzyl substitution. We previously evaluated the substitution effects on the menadione core (i.e., the western region of the 3‐benz(o)ylmenadione derivatives) and found that the two one‐electron transfers were sensitive to the nature of the substituent and the position of substitution . The redox potentials of the substituted 3‐benz(o)ylmenadiones (Table and Figures S3–S42) were measured by CV (Table ) and SWV (Table S3) at 25 °C using a glassy carbon electrode in DMSO solvent and tetra‐ n ‐butylammonium hexafluorophosphate [N( n Bu) 4 PF 6 ] as the supporting electrolyte.…”

Section: Resultsmentioning

confidence: 99%

“…Therefore, a model based on simpler molecular descriptors is desirable. Recently, our group has reported the possibilities of QSPR modeling for prediction of the redox potential of substituted 2‐methyl‐1,4‐naphthoquinones (menadiones) . An online evaluation model was built and made available to predict the electrochemical properties of these quinones and redox‐active analogues to aid medicinal chemists in targeting their synthetic efforts toward redox‐active agents.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Redox Polypharmacology as an Emerging Strategy to Combat Malarial Parasites

et al. 2016

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“…Efficient synthetic methodologies have been established (4,5) and will allow preparation of a large array of diverse benzylmenadiones for further structureactivity relationship investigations. Already developed chemoinformatic tools are available for predicting the redox potentials of polysubstituted menadiones (6,7). Application of these tools to the polysubstituted benz(o)ylmenadiones will be instrumental in predicting their oxidant character and other molecular descriptors in order to guide synthetic efforts toward analogues with desired properties (7).…”

Section: Discussionmentioning

confidence: 99%

“…The synthesis of plasmodione is achieved in only one step from cheap commercially available starting materials, and its low-molecular-weight structure provides a large chemical space for optimization by derivatization (3). Its structure served as a starting point for development of chemical optimization strategies aimed at generating benzylmenadione derivatives with superior pharmacokinetic or pharmacodynamic properties (4)(5)(6)(7).…”

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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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“…Nonetheless, non-conducting films are typically formed by a few units of impermeable dimers or oligomers, subsequently producing few electroactive sites [9,10], such as in the dimerization of aniline [11][12][13], phenol [14][15][16] and quinones [17][18][19]. In this letter, we report the successful electrochemical synthesis of a conductive dapsone polymer using cyclic voltammetry in a lower potential window and high scan rates.…”

Section: Introductionmentioning

confidence: 99%

Conductive organic polymers: An electrochemical route for the polymerization of dapsone

Moura

Júnior

Machado

et al. 2015

Journal of Electroanalytical Chemistry

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The electropolymerization of dapsone by anodic oxidation is reported for the first time. The conditions in which a non-conducting oligomeric film or a conductive polymeric film of dapsone is formed are also discussed, based on the scan rate and potential window applied. The cyclic voltammetry of dapsone-polymer presented redox activities that have not been shown before, to the authors' knowledge, demonstrating its high electronic conductivity. The electrochemical impedance response of the dapsone-polymer indicates that their admittance is similar to pure and sulfonated polyanilines, while for the dapsone-oligomers is characteristic of insulating materials. Infrared spectroscopy of both oligomers and polymer supports that the polymerization occurs via amino-amino coupling, since no modifications in the aromatic ring is observed.KEYWORDS. polydapsone, electropolymerization, conductive polymer, Fe +3 /Fe +2 redox couple, polyaniline. Graphical abstract -0.2 0.0 0.2 0.4 0.6 0.8 -50 -40 -30 -20 -10 0 10 20 30 40 GCE GCE/Dapsone-Polymer GCE/Dapsone-Oligomers E / V (vs. Ag/AgCl) Fe +3 /Fe +2 redox couple

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Electrochemical Properties of Substituted 2‐Methyl‐1,4‐Naphthoquinones: Redox Behavior Predictions

Cited by 38 publications

References 88 publications

Redox Polypharmacology as an Emerging Strategy to Combat Malarial Parasites

Redox Polypharmacology as an Emerging Strategy to Combat Malarial Parasites

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

Conductive organic polymers: An electrochemical route for the polymerization of dapsone

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