title: Synthesis and in vitro evaluation of 4-trichloromethylpyrrolo[1,2-a]quinoxalines as new antiplasmodial agents.
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.
authors.affiliation: 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.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Primas
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, FR CNRS INC3M, Boulevard Becquerel, 14032 Caen, France.
authors.forename: Peggy
authors.initials: P
authors.lastname: Suzanne
authors.affiliation: Université Paul Sabatier, Faculté des Sciences Pharmaceutiques - CNRS UPR 8241, Laboratoire de Chimie de Coordination, 205 Route de Narbonne, 31077 Toulouse Cedex 04, France.
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, Laboratoire de 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: Michèle
authors.initials: M
authors.lastname: Laget
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: 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.
authors.forename: Julie
authors.initials: J
authors.lastname: Broggi
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, FR CNRS INC3M, Boulevard Becquerel, 14032 Caen, France.
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Lancelot
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, FR CNRS INC3M, Boulevard Becquerel, 14032 Caen, France.
authors.forename: Aurélien
authors.initials: A
authors.lastname: Lesnard
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, FR CNRS INC3M, Boulevard Becquerel, 14032 Caen, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Dallemagne
authors.affiliation: 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.
authors.forename: Pascal
authors.initials: P
authors.lastname: Rathelot
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, FR CNRS INC3M, Boulevard Becquerel, 14032 Caen, France.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Rault
authors.affiliation: 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.
authors.forename: Patrice
authors.initials: P
authors.lastname: Vanelle
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
mesh_terms: D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D060326:Chemistry Techniques, Synthetic; D056945:Hep G2 Cells; D006801:Humans; D008745:Methylation; D010963:Plasmodium falciparum / Q000187:drug effects*; D011810:Quinoxalines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity
chemical_list: D000962:Antimalarials; D011810:Quinoxalines
keywords: In vitro HepG2 cytotoxicity; In vitro antiplasmodial activity; Plasmodium falciparum; Pyrrolo[1,2-a]quinoxaline; SARs; Trichloromethyl goup