title: Targeting the human malaria parasite Plasmodium falciparum: in vitro identification of a new antiplasmodial hit in 4-phenoxy-2-trichloromethylquinazoline series.
abstract: From the promising results we previously obtained in quinazoline series and to complete the evaluation of the in vitro antiplasmodial activity of original 2-trichloromethylquinazolines, we synthesized new quinazolines possessing a variously substituted phenoxy group at position 4 through a simple and efficient two-step-synthesis approach. The studies of their activity toward the multi-resistant W2 Plasmodium falciparum strain and of their cytotoxicity on the human hepatocyte HepG2 cell line highlighted a hit compound (molecule 7) displaying a W2 IC(50) value of 1.1 μM and a HepG2 CC(50) value of 50 μM, comparable to chloroquine and doxycycline. Structure-activity- and toxicity relationships indicate that the trichloromethyl group plays a key role in the antiplasmodial activity of such chemical scaffold and also that the phenoxy group substitution as a direct influence on the molecules selectivity. Moreover, molecule 7 displays significant specific activity against the Plasmodium genus in comparison with Toxoplasma and does not show any mutagenic property at the Ames test.
authors: Laboratoire de Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, Universités d'Aix-Marseille I, II et III - UMR CNRS 6264, Laboratoire Chimie Provence, 27 Boulevard Jean Moulin, 13385 Marseille cedex 05, France.
authors: Caroline
authors: C
authors: Castera-Ducros
authors: Nadine
authors: N
authors: Azas
authors: Pierre
authors: P
authors: Verhaeghe
authors: Sébastien
authors: S
authors: Hutter
authors: Philippe
authors: P
authors: Garrigue
authors: Aurélien
authors: A
authors: Dumètre
authors: Litaty
authors: L
authors: Mbatchi
authors: Michèle
authors: M
authors: Laget
authors: Vincent
authors: V
authors: Remusat
authors: France
authors: F
authors: Sifredi
authors: Sylvain
authors: S
authors: Rault
authors: Pascal
authors: P
authors: Rathelot
authors: Patrice
authors: P
authors: Vanelle
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D002460:Cell Line; D006801:Humans; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D010963:Plasmodium falciparum / Q000187:drug effects*; D011799:Quinazolines / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D013329:Structure-Activity Relationship
chemical_list: C568944:4-(4-chlorophenoxy)-2-trichloromethylquinazoline; D000962:Antimalarials; D011799:Quinazolines