title: Interaction of sitamaquine with membrane lipids of Leishmania donovani promastigotes.
abstract: Sitamaquine is an 8-aminoquinoline which is active by the oral route for the treatment of life-threatening visceral leishmaniasis caused by Leishmania donovani, with an IC50 of 29.2 microM against the promastigote form in vitro. At high concentration (100 microM), sitamaquine affected parasite motility, morphology and growth in a way that was only partially reversible. As a first approach to determine its mechanism of action, we describe the interaction of sitamaquine with parasite membrane components, representing the first barrier to be crossed by the drug. Analysis of the physicochemical interactions of sitamaquine with monolayers of phospholipids and sterols at the air-water interface showed that these interactions only occurred in the presence of anionic phospholipids. Thus, electrostatic interactions between positively charged sitamaquine and the negative polar headgroups are a pre-requisite for subsequent hydrophobic interactions between the sitamaquine aromatic ring and the alkyl chains of phospholipids leading to drug insertion into the monolayer.
authors.affiliation: Groupe Chimiothérapie Antiparasitaire, UMR 8076 CNRS, Faculté de Pharmacie, Université Paris-Sud XI, rue Jean-Baptiste Clément, F-92290-Châtenay-Malabry, France.
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Dueñas-Romero
authors.forename: Philippe M
authors.initials: PM
authors.lastname: Loiseau
authors.forename: Michèle
authors.initials: M
authors.lastname: Saint-Pierre-Chazalet
mesh_terms: D000388:Air; D000634:Aminoquinolines / Q000494:pharmacology*; D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology*; D002462:Cell Membrane / Q000378:metabolism*; D004347:Drug Interactions; D007893:Leishmania donovani / Q000187:drug effects* / Q000254:growth & development; D007898:Leishmaniasis, Visceral / Q000188:drug therapy / Q000469:parasitology; D008563:Membrane Lipids / Q000378:metabolism*; D010743:Phospholipids / Q000378:metabolism; D055672:Static Electricity; D013261:Sterols / Q000378:metabolism; D014867:Water / Q000737:chemistry
chemical_list: D000634:Aminoquinolines; D000981:Antiprotozoal Agents; D008563:Membrane Lipids; D010743:Phospholipids; D013261:Sterols; D014867:Water; C080436:8-aminoquinoline