title: Looking for new antileishmanial derivatives in 8-nitroquinolin-2(1H)-one series.
abstract: From a recently identified antileishmanial pharmacophore, a structure-activity relationship study was conducted by introducing various aminated, phenoxy or thiophenoxy moieties at position 4 of the 8-nitroquinolin-2(1H)-one scaffold, using SNAr reactions. Thus a series of 47 derivatives was synthesized and evaluated in vitro on the promastigote stage of Leishmania donovani. In parallel, the cytotoxicity of the active molecules was tested on the human HepG2 cell line. The results we obtained showed that the introduction of a substituent at position 4 of the antileishmanial pharmacophore can either lead to inactive or active derivatives, depending on the nature of the substituent. Aminated moieties appear as very unfavorable toward antileishmanial activity, while phenoxy or thiophenoxy moieties were shown to maintain the in vitro antileishmanial profile, especially when the phenyl ring of these moieties was substituted at the para or ortho position by a halogen atom (except fluorine), a trifluoromethyl group or a methyl group. Most of these derivatives showed a lack of solubility in the culture media which hindered the in vitro determination of both their cytotoxicity and activity against the intracellular amastigoste stage of L. donovani.
authors.affiliation: Aix-Marseille Université, CNRS, ICR UMR 7273, Equipe Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, 27 Boulevard Jean Moulin - CS30064, 13385 Marseille Cedex 05, France.
authors.forename: Charline
authors.initials: C
authors.lastname: Kieffer
authors.affiliation: Aix-Marseille Université, UMR MD 3, Infections Parasitaires, Transmission et Thérapeutique, Faculté de Pharmacie, 27 Boulevard Jean Moulin - CS30064, 13385 Marseille Cedex 05, France.
authors.forename: Anita
authors.initials: A
authors.lastname: Cohen
authors.affiliation: Université Paul Sabatier, CNRS UPR 8241, Laboratoire de Chimie de Coordination (LCC)- Faculté des Sciences Pharmaceutiques, 205 Route de Narbonne, 31077 Toulouse Cedex 04, France. Electronic address: pierre.verhaeghe@univ-tlse3.fr.
authors.forename: Pierre
authors.initials: P
authors.lastname: Verhaeghe
authors.affiliation: Aix-Marseille Université, UMR MD 3, Infections Parasitaires, Transmission et Thérapeutique, Faculté de Pharmacie, 27 Boulevard Jean Moulin - CS30064, 13385 Marseille Cedex 05, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Hutter
authors.affiliation: Aix-Marseille Université, CNRS, ICR UMR 7273, Equipe Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, 27 Boulevard Jean Moulin - CS30064, 13385 Marseille Cedex 05, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Castera-Ducros
authors.affiliation: Aix-Marseille Université, UMR MD 3, Infections Parasitaires, Transmission et Thérapeutique, Faculté de Pharmacie, 27 Boulevard Jean Moulin - CS30064, 13385 Marseille Cedex 05, France.
authors.forename: Michèle
authors.initials: M
authors.lastname: Laget
authors.affiliation: Aix-Marseille Université, CNRS, ICR UMR 7273, Equipe Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, 27 Boulevard Jean Moulin - CS30064, 13385 Marseille Cedex 05, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Remusat
authors.affiliation: Aix-Marseille Université, CNRS, ICR UMR 7273, Equipe Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, 27 Boulevard Jean Moulin - CS30064, 13385 Marseille Cedex 05, France.
authors.forename: Manel Kraiem
authors.initials: MK
authors.lastname: M'Rabet
authors.affiliation: Université de Caen Basse Normandie, Faculté des Sciences Pharmaceutiques, Centre d'Etudes et de Recherche sur le Médicament de Normandie (CERMN) - EA 4258, Boulevard Becquerel, 14032 Caen, France.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Rault
authors.affiliation: Aix-Marseille Université, CNRS, ICR UMR 7273, Equipe Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, 27 Boulevard Jean Moulin - CS30064, 13385 Marseille Cedex 05, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Rathelot
authors.affiliation: Aix-Marseille Université, UMR MD 3, Infections Parasitaires, Transmission et Thérapeutique, Faculté de Pharmacie, 27 Boulevard Jean Moulin - CS30064, 13385 Marseille Cedex 05, France. Electronic address: nadine.azas@univ-amu.fr.
authors.forename: Nadine
authors.initials: N
authors.lastname: Azas
authors.affiliation: Aix-Marseille Université, CNRS, ICR UMR 7273, Equipe Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, 27 Boulevard Jean Moulin - CS30064, 13385 Marseille Cedex 05, France.
authors.forename: Patrice
authors.initials: P
authors.lastname: Vanelle
mesh_terms: D000981:Antiprotozoal Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D007893:Leishmania donovani / Q000187:drug effects*; D015394:Molecular Structure; D009600:Nitroquinolines / Q000737:chemistry*; D021261:Parasitic Sensitivity Tests; D013329:Structure-Activity Relationship
chemical_list: D000981:Antiprotozoal Agents; D009600:Nitroquinolines
keywords: Leishmaniasis; Nitro group; Quinoline ring; SARs