2. Academic Validation
  3. Discovery of new hit-molecules targeting Plasmodium falciparum through a global SAR study of the 4-substituted-2-trichloromethylquinazoline antiplasmodial scaffold

Discovery of new hit-molecules targeting Plasmodium falciparum through a global SAR study of the 4-substituted-2-trichloromethylquinazoline antiplasmodial scaffold

  • Eur J Med Chem. 2017 Jan 5:125:68-86. doi: 10.1016/j.ejmech.2016.09.029.
Justine Desroches 1,  Charline Kieffer 1,  Nicolas Primas 1,  Sébastien Hutter 2,  Armand Gellis 1,  Hussein El-Kashef 3,  Pascal Rathelot 1,  Pierre Verhaeghe 4,  Nadine Azas 2,  Patrice Vanelle 5
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 MD3, Infections Parasitaires, Transmission et Thérapeutique, Faculté de Pharmacie, 27 Boulevard Jean Moulin - CS30064, 13385 Marseille Cedex 05, France.
  • 3 Department of Chemistry, Faculty of Science, Assiut University, 71516 Assiut, Egypt.
  • 4 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.
  • 5 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.
PMID: 27654395 DOI: 10.1016/j.ejmech.2016.09.029
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.

Keywords

In vitro HepG2 cytotoxicity; In vitro antiplasmodial activity; Plasmodium falciparum; Quinazoline; Quinoline; Quinoxaline; Structure-activity relationships; Thienopyrimidine; Trichloromethyl goup.

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