title: Exploring the trifluoromenadione core as a template to design antimalarial redox-active agents interacting with glutathione reductase.
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 CF(3) as a leaving group. The resulting trifluoromethyl derivative 5 showed a potent antimalarial activity per se against malarial parasites in culture.
authors.affiliation: European School of Chemistry, Polymers and Materials, University of Strasbourg, UMR CNRS 7509, 25 Rue Becquerel, F-67087 Strasbourg, France.
authors.forename: Don Antoine
authors.initials: DA
authors.lastname: Lanfranchi
authors.forename: Didier
authors.initials: D
authors.lastname: Belorgey
authors.forename: Tobias
authors.initials: T
authors.lastname: Müller
authors.forename: Hervé
authors.initials: H
authors.lastname: Vezin
authors.forename: Michael
authors.initials: M
authors.lastname: Lanzer
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Davioud-Charvet
mesh_terms: D000962:Antimalarials / Q000138:chemical synthesis* / Q000494:pharmacology; D055162:Biocatalysis; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D017611:Fluorine Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D005980:Glutathione Reductase / Q000037:antagonists & inhibitors*; D006801:Humans; D015394:Molecular Structure; D010084:Oxidation-Reduction; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology; D013329:Structure-Activity Relationship; D024483:Vitamin K 3 / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D000962:Antimalarials; D004791:Enzyme Inhibitors; D017611:Fluorine Compounds; D024483:Vitamin K 3; D005980:Glutathione Reductase