Original article Antileishmanial 2-substituted quinolines: In vitro behaviour towards biological components Julie Desrivot a , Christine Herrenknecht a , Gilles Ponchel b , Najla Garbi b , Eric Prina c , Alain Fournet d , Christian Bories a , Bruno Figade `re a , Reynald Hocquemiller a , Philippe M. Loiseau a, * a Laboratoire de Pharmacognosie et Chimiothe ´rapie Antiparasitaire, Centre d’Etudes Pharmaceutiques, BioCIS UMR 8076, Universite ´ Paris-Sud 11, 5 rue J-B Cle ´ment, 92290 Cha ˆtenay-Malabry, France b Laboratoire de Pharmacotechnie et Biopharmacie, Centre d’Etudes Pharmaceutiques, UMR CNRS 8612, Universite ´ Paris-Sud 11, 5 rue J-B Cle ´ment, 92290 Cha ˆtenay-Malabry, France c Unite ´ d’Immunophysiologie et Parasitisme Intracellulaire, Institut Pasteur, 25 rue du Dr. Roux, 75724 Paris Cedex 15, France d Laboratoire de Pharmacognosie, Centre d’Etudes Pharmaceutiques, IRD US 084, Universite ´ Paris-Sud 11, 5 rue J-B Cle ´ment, 92290 Cha ˆ tenay-Malabry, France Received 28 February 2007; accepted 9 March 2007 Available online 2 April 2007 Abstract Quinolines substituted on their carbon 2 have in vivo antileishmanial activity but some of them could not be detected in plasma when assayed for pharmacokinetic studies, suggesting a sequestration of the drugs by components of the blood compartment. The present study, performed on three quinolines (1, 2 and 3), showed strong affinity for two of them (2 and 3) with red blood cells (RBCs), whereas quinoline 1 did not react with them. This process was saturable, temperature dependant and positively correlated with the in vitro antileishmanial activity of the quino- lines. In addition, a rapid and spontaneous reaction with thiol groups was demonstrated for unsaturated quinolines 2 and 3. The reactivity with RBCs could be part of the compounds targeting to the parasite. These results illustrate that derivatives of the quinoline series with similar anti- leishmanial in vivo activity have different behaviour in the blood compartment. Ó 2007 Elsevier Masson SAS. All rights reserved. Keywords: 2-Substituted quinolines; In vitro interaction 1. Introduction Leishmaniases are a complex of parasitic diseases due to the infection of mammals by a parasite of the Leishmania genus. Several species are responsible of multiple clinical forms. The visceral form (VL) is the most severe because of its lethality if not treated. Endemic zones being mostly in developing coun- tries, more than 90% of patients with VL die untreated. Ranked among the six most important tropical infectious diseases by the World Health Organization, 350 million people live in endemic zones, 12 million people are infected worldwide and there are 2 million new cases each year [1,2] Indeed, classical treatments are expensive, toxic, and require parenteral administration (an- timonials and liposomal amphotericin B). The recent disposal of miltefosine, the first drug active by oral route, is really a progress but drug resistance is at risk [3]. Therefore there is an urgent need to develop new per os treatments. We previously isolated a series of 2-substituted quinolines from a Bolivian tree, Galipea longiflora (Rutaceae), tradition- ally used to cure ulcerations of cutaneous leishmaniasis by the native Chimane Indians [4]. These compounds showed anti- leishmanial properties on an in vivo mouse model of VL after * Corresponding author. Tel.: þ33 1 46 83 55 53; fax: þ33 1 46 83 55 57. E-mail address: philippe.loiseau@u-psud.fr (P.M. Loiseau). 0753-3322/$ - see front matter Ó 2007 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.biopha.2007.03.004 Biomedicine & Pharmacotherapy 61 (2007) 441e450 www.elsevier.com/locate/biopha