2. Academic Validation
  3. Synthesis and in vitro evaluation of 4-trichloromethylpyrrolo[1,2-a]quinoxalines as new antiplasmodial agents

Synthesis and in vitro evaluation of 4-trichloromethylpyrrolo[1,2-a]quinoxalines as new antiplasmodial agents

  • Eur J Med Chem. 2014 Aug 18:83:26-35. doi: 10.1016/j.ejmech.2014.06.014.
Nicolas Primas 1,  Peggy Suzanne 2,  Pierre Verhaeghe 3,  Sébastien Hutter 4,  Charline Kieffer 1,  Michèle Laget 4,  Anita Cohen 4,  Julie Broggi 1,  Jean-Charles Lancelot 2,  Aurélien Lesnard 2,  Patrick Dallemagne 2,  Pascal Rathelot 1,  Sylvain Rault 2,  Patrice Vanelle 5,  Nadine Azas 6
Affiliations

Affiliations

  • 1 Aix-Marseille Université, CNRS, ICR UMR 7273, Laboratoire de Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, 27 Boulevard Jean Moulin - CS30064, 13385 Marseille Cedex 05, France.
  • 2 Université de Caen Basse Normandie, Faculté des Sciences Pharmaceutiques, Centre d'Etudes et de Recherche sur le Médicament de Normandie (CERMN) - EA 4258, FR CNRS INC3M, Boulevard Becquerel, 14032 Caen, France.
  • 3 Université Paul Sabatier, Faculté des Sciences Pharmaceutiques - CNRS UPR 8241, Laboratoire de Chimie de Coordination, 205 Route de Narbonne, 31077 Toulouse Cedex 04, France.
  • 4 Aix-Marseille Université, UMR MD 3, Infections Parasitaires, Transmission et Thérapeutique, Faculté de Pharmacie, 27 Boulevard Jean Moulin - CS30064, 13385 Marseille Cedex 05, France.
  • 5 Aix-Marseille Université, CNRS, ICR UMR 7273, Laboratoire de Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, 27 Boulevard Jean Moulin - CS30064, 13385 Marseille Cedex 05, France. Electronic address: patrice.vanelle@univ-amu.fr.
  • 6 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: 24946216 DOI: 10.1016/j.ejmech.2014.06.014
Abstract

Thanks to a preliminary in vitro screening of several CCl3-substituted-nitrogen containing heterocycles belonging to our chemical library, the 2-trichloromethylquinoxaline scaffold appeared to be of potential interest for developing new antiplasmodial agents. Then, combining these experimental results to the antimalarial properties reported for various pyrrolo[1,2-a]quinoxaline derivatives, an original series of fifteen 7-substituted-4-trichoromethylpyrrolo[1,2-a]quinoxalines was synthesized in a 4 to 5 reaction steps pathway. All molecules were evaluated in vitro toward both their antiplasmodial activity on the K1 multi-resistant Plasmodium falciparum strain and their cytotoxicity on the HepG2 human cell line. Thus, 3 hit molecules were identified, displaying IC50 values in the micromolar range and low cytotoxicity values, reaching good selectivity indexes, in comparison with the reference drugs chloroquine and doxycycline. Structure-activity relationship studies showed that the pyrrolo[1,2-a]quinoxaline scaffold can support selective antiplasmodial activity when substituted at position 4 by a CCl3 group. However, substitution at position 7 of the same scaffold is neither beneficial for cytotoxicity nor favourable for the solubility in the biological media.

Keywords

In vitro HepG2 cytotoxicity; In vitro antiplasmodial activity; Plasmodium falciparum; Pyrrolo[1,2-a]quinoxaline; SARs; Trichloromethyl goup.

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