title: Redox Polypharmacology as an Emerging Strategy to Combat Malarial Parasites.
abstract: 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.
authors.affiliation: Laboratoire de Chemoinformatique, UMR 7140 CNRS-Université de Strasbourg, 1 rue Blaise Pascal, Strasbourg, 67000, France.|Butlerov Institute of Chemistry, Kazan Federal University, 1/29 Lobachevskogo str., Kazan, 420008, Russia.
authors.forename: Pavel
authors.initials: P
authors.lastname: Sidorov
authors.affiliation: Laboratoire de Chimie Bioorganique et Medicinale, UMR 7509 CNRS-Université de Strasbourg, European School of Chemistry, Polymers and Materials (ECPM), 25 Rue Becquerel, 67087, Strasbourg, France.|New York University Abu Dhabi (NYUAD), Saadiyat Island, Abu Dhabi, UAE.
authors.forename: Israel
authors.initials: I
authors.lastname: Desta
authors.affiliation: Laboratoire de Chimie Bioorganique et Medicinale, UMR 7509 CNRS-Université de Strasbourg, European School of Chemistry, Polymers and Materials (ECPM), 25 Rue Becquerel, 67087, Strasbourg, France.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Chessé
authors.affiliation: Laboratoire de Chemoinformatique, UMR 7140 CNRS-Université de Strasbourg, 1 rue Blaise Pascal, Strasbourg, 67000, France.
authors.forename: Dragos
authors.initials: D
authors.lastname: Horvath
authors.affiliation: Laboratoire de Chemoinformatique, UMR 7140 CNRS-Université de Strasbourg, 1 rue Blaise Pascal, Strasbourg, 67000, France.
authors.forename: Gilles
authors.identifier: 0000-0003-1676-6708
authors.initials: G
authors.lastname: Marcou
authors.affiliation: Laboratoire de Chemoinformatique, UMR 7140 CNRS-Université de Strasbourg, 1 rue Blaise Pascal, Strasbourg, 67000, France.
authors.forename: Alexandre
authors.identifier: 0000-0003-1886-925X
authors.initials: A
authors.lastname: Varnek
authors.affiliation: Laboratoire de Chimie Bioorganique et Medicinale, UMR 7509 CNRS-Université de Strasbourg, European School of Chemistry, Polymers and Materials (ECPM), 25 Rue Becquerel, 67087, Strasbourg, France. elisabeth.davioud@unistra.fr.
authors.forename: Elisabeth
authors.identifier: 0000-0001-7026-4034
authors.initials: E
authors.lastname: Davioud-Charvet
authors.affiliation: Laboratoire de Chimie Bioorganique et Medicinale, UMR 7509 CNRS-Université de Strasbourg, European School of Chemistry, Polymers and Materials (ECPM), 25 Rue Becquerel, 67087, Strasbourg, France. elhabiri@unistra.fr.
authors.forename: Mourad
authors.initials: M
authors.lastname: Elhabiri
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000494:pharmacology* / Q000627:therapeutic use*; D006801:Humans; D008288:Malaria / Q000188:drug therapy*; D010084:Oxidation-Reduction; D010961:Plasmodium / Q000187:drug effects*; D019338:Polypharmacy
chemical_list: D000962:Antimalarials
keywords: QSPR; chemoinformatics; menadione; multitarget drugs; redox potential