title: Selection of a trioxaquine as an antimalarial drug candidate.
abstract: Trioxaquines are antimalarial agents based on hybrid structures with a dual mode of action. One of these molecules, PA1103/SAR116242, is highly active in vitro on several sensitive and resistant strains of Plasmodium falciparum at nanomolar concentrations (e.g., IC(50) value = 10 nM with FcM29, a chloroquine-resistant strain) and also on multidrug-resistant strains obtained from fresh patient isolates in Gabon. This molecule is very efficient by oral route with a complete cure of mice infected with chloroquine-sensitive or chloroquine-resistant strains of Plasmodia at 26-32 mg/kg. This compound is also highly effective in humanized mice infected with P. falciparum. Combined with a good drug profile (preliminary absorption, metabolism, and safety parameters), these data were favorable for the selection of this particular trioxaquine for development as drug candidate among 120 other active hybrid molecules.
authors.affiliation: Palumed, Rue Pierre et Marie Curie, BP 28262, F-31682 Labège Cedex, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Coslédan
authors.forename: Laurent
authors.initials: L
authors.lastname: Fraisse
authors.forename: Alain
authors.initials: A
authors.lastname: Pellet
authors.forename: François
authors.initials: F
authors.lastname: Guillou
authors.forename: Benjamin
authors.initials: B
authors.lastname: Mordmüller
authors.forename: Peter G
authors.initials: PG
authors.lastname: Kremsner
authors.forename: Alicia
authors.initials: A
authors.lastname: Moreno
authors.forename: Dominique
authors.initials: D
authors.lastname: Mazier
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Maffrand
authors.forename: Bernard
authors.initials: B
authors.lastname: Meunier
mesh_terms: D000634:Aminoquinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D003461:Crystallography; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D055808:Drug Discovery; D004594:Electrophysiology; D006418:Heme / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D015162:Micronucleus Tests; D015394:Molecular Structure; D010963:Plasmodium falciparum / Q000187:drug effects*
chemical_list: D000634:Aminoquinolines; D000962:Antimalarials; D006418:Heme; D003577:Cytochrome P-450 Enzyme System