Original quinazoline derivatives displaying antiplasmodial properties.
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.
Kabri
Youssef
Y
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.
Azas
Nadine
N
Dumètre
Aurélien
A
Hutter
Sébastien
S
Laget
Michèle
M
Verhaeghe
Pierre
P
Gellis
Armand
A
Vanelle
Patrice
P
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
D000814:Aniline Compounds; D000981:Antiprotozoal Agents; D011799:Quinazolines; D010770:Phosphotransferases; C023650:aniline