title: Original quinazoline derivatives displaying antiplasmodial properties.
abstract: The multistep synthesis of new quinazoline-derived molecules and their in vitro antiplasmodial evaluation on the W2 chloroquino-resistant Plasmodium falciparum strain is described herein. These molecules have also been studied concerning their in vitro cytotoxicity toward two human cell lines (K652 and HepG2) in order to calculate their respective selectivity indexes (S.I.). Among the fourteen tested molecules, two exhibited both significant antiplasmodial activity (IC(50)=0.95 and 1.3 microM) and low toxicity (IC(50)>100 or 125 microM), compared with two reference drugs: chloroquine and doxycycline. The structure activity relationships establish that the molecular scaffold which exerts the best profile is the 6-nitro-2-(tosylmethyl)-N-(3-substituted-phenyl)-quinazolin-4-amine. The hit molecules were finally investigated regarding their potential action toward two other protozoa, Leishmania donovani and Toxoplasma gondii, showing that these molecules display a selective antiplasmodial activity.
authors.affiliation: Laboratoire de Pharmacochimie 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.forename: Youssef
authors.initials: Y
authors.lastname: Kabri
authors.forename: Nadine
authors.initials: N
authors.lastname: Azas
authors.forename: Aurélien
authors.initials: A
authors.lastname: Dumètre
authors.forename: Sébastien
authors.initials: S
authors.lastname: Hutter
authors.forename: Michèle
authors.initials: M
authors.lastname: Laget
authors.forename: Pierre
authors.initials: P
authors.lastname: Verhaeghe
authors.forename: Armand
authors.initials: A
authors.lastname: Gellis
authors.forename: Patrice
authors.initials: P
authors.lastname: Vanelle
mesh_terms: D000814:Aniline Compounds / Q000737:chemistry; D000818:Animals; D000981:Antiprotozoal Agents / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D002460:Cell Line; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D007893:Leishmania donovani / Q000187:drug effects; D010770:Phosphotransferases / Q000037:antagonists & inhibitors; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology; D011799:Quinazolines / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D014122:Toxoplasma / Q000187:drug effects
chemical_list: D000814:Aniline Compounds; D000981:Antiprotozoal Agents; D011799:Quinazolines; D010770:Phosphotransferases; C023650:aniline