Exploring the trifluoromenadione core as a template to design antimalarial redox-active agents interacting with glutathione reductase

• Verfasst von: Lanfranchi, Don A. [VerfasserIn]
• Verfasst von: Müller, Tobias [VerfasserIn]
• Verfasst von: Lanzer, Michael [VerfasserIn]
• Verfasst von: Davioud-Charvet, Elisabeth [VerfasserIn]
• Titel: Exploring the trifluoromenadione core as a template to design antimalarial redox-active agents interacting with glutathione reductase
• Verf.angabe: Don Antoine Lanfranchi, Didier Belorgey, Tobias Müller, Hervé Vezin, Michael Lanzer, Elisabeth Davioud-Charvet
• E-Jahr: 2012
• Jahr: 17 Apr 2012
• Umfang: 12 S.
• Fussnoten: Gesehen am 18.10.2018
• Titel Quelle: Enthalten in: Organic & biomolecular chemistry
• Ort Quelle: Cambridge : Royal Society of Chemistry, 2003
• Jahr Quelle: 2012
• Band/Heft Quelle: 10(2012), 24, Seite 4795-4806
• ISSN Quelle: 1477-0539
• DOI: doi:10.1039/C2OB25229E
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1582083401

Abstract

Menadione is the 2-methyl-1,4-naphthoquinone core used to design potent antimalarial redox-cyclers to affect the redox equilibrium of Plasmodium-infected red blood cells. Exploring the reactivity of fluoromethyl-1,4-naphthoquinones, in particular trifluoromenadione, under quasi-physiological conditions in NADPH-dependent glutathione reductase reactions, is discussed in terms of chemical synthesis, electrochemistry, enzyme kinetics, and antimalarial activities. Multitarget-directed drug discovery is an emerging approach to the design of new antimalarial drugs. Combining in one single 1,4-naphthoquinone molecule, the trifluoromenadione core with the alkyl chain at C-3 of the known antimalarial drug atovaquone, revealed a mechanism for CF3 as a leaving group. The resulting trifluoromethyl derivative 5 showed a potent antimalarial activity per se against malarial parasites in culture.