2. Academic Validation
  3. Looking for new antileishmanial derivatives in 8-nitroquinolin-2(1H)-one series

Looking for new antileishmanial derivatives in 8-nitroquinolin-2(1H)-one series

  • Eur J Med Chem. 2015 Mar 6:92:282-94. doi: 10.1016/j.ejmech.2014.12.056.
Charline Kieffer 1,  Anita Cohen 2,  Pierre Verhaeghe 3,  Sébastien Hutter 2,  Caroline Castera-Ducros 1,  Michèle Laget 2,  Vincent Remusat 1,  Manel Kraiem M'Rabet 1,  Sylvain Rault 4,  Pascal Rathelot 1,  Nadine Azas 5,  Patrice Vanelle 1
Affiliations

Affiliations

  • 1 Aix-Marseille Université, CNRS, ICR UMR 7273, Equipe Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, 27 Boulevard Jean Moulin - CS30064, 13385 Marseille Cedex 05, France.
  • 2 Aix-Marseille Université, UMR MD 3, Infections Parasitaires, Transmission et Thérapeutique, Faculté de Pharmacie, 27 Boulevard Jean Moulin - CS30064, 13385 Marseille Cedex 05, France.
  • 3 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.
  • 4 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.
  • 5 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.
PMID: 25559208 DOI: 10.1016/j.ejmech.2014.12.056
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.

Keywords

Leishmaniasis; Nitro group; Quinoline ring; SARs.

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