title: Discovery of new hit-molecules targeting Plasmodium falciparum through a global SAR study of the 4-substituted-2-trichloromethylquinazoline antiplasmodial scaffold.
abstract: From 4 antiplasmodial hit-molecules identified in 2-trichloromethylquinazoline series, we conducted a global Structure-Activity relationship (SAR) study involving 26 compounds and covering 5 molecular regions (I - V), aiming at defining the corresponding pharmacophore and identifying new bioactive derivatives. Thus, after studying the aniline moiety in detail, thienopyrimidine, quinoline and quinoxaline bio-isosters were synthesized and tested on the K1 multi-resistant P. falciparum strain, along with a cytotoxicity evaluation on the human HepG2 cell line, to define selectivity indecies. SARs first showed that thienopyrimidines and quinolines were globally more cytotoxic, while quinoxaline analogs appeared as active as- and less cytotoxic than their quinazoline counterparts. Such pharmacomodulation in quinoxaline series not only provided a new antiplasmodial reference hit-molecule (IC50= 0.4 μM, selectivity index = 100), but also highlighted an active (IC50= 0.4 μM) and quite selective (SI = 265) synthesis intermediate.
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: Justine
authors.initials: J
authors.lastname: Desroches
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, CNRS, ICR UMR 7273, Equipe 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: Aix-Marseille Université, UMR MD3, 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: Armand
authors.initials: A
authors.lastname: Gellis
authors.affiliation: Department of Chemistry, Faculty of Science, Assiut University, 71516 Assiut, Egypt.
authors.forename: Hussein
authors.initials: H
authors.lastname: El-Kashef
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: Université Paul Sabatier, Faculté des Sciences Pharmaceutiques - CNRS UPR 8241, Laboratoire de Chimie de Coordination, 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 MD3, Infections Parasitaires, Transmission et Thérapeutique, Faculté de Pharmacie, 27 Boulevard Jean Moulin - CS30064, 13385 Marseille Cedex 05, France.
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. Electronic address: patrice.vanelle@univ-amu.fr.
authors.forename: Patrice
authors.initials: P
authors.lastname: Vanelle
mesh_terms: D000962:Antimalarials / Q000138:chemical synthesis* / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D055808:Drug Discovery; D056945:Hep G2 Cells; D006801:Humans; D010963:Plasmodium falciparum / Q000187:drug effects*; D011799:Quinazolines / Q000138:chemical synthesis / Q000494:pharmacology*; D012680:Sensitivity and Specificity; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D011799:Quinazolines
keywords: In vitro HepG2 cytotoxicity; In vitro antiplasmodial activity; Plasmodium falciparum; Quinazoline; Quinoline; Quinoxaline; Structure-activity relationships; Thienopyrimidine; Trichloromethyl goup