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.
Eur J Med Chem. 2010 Feb;45(2):616-22. doi: 10.1016/j.ejmech.2009.11.005. Epub 2009 Nov 6.
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.
本文描述了新的喹唑啉衍生分子的多步合成及其对 W2 氯喹耐药恶性疟原虫株的体外抗疟活性评价。还研究了这些分子的体外细胞毒性，以计算其各自的选择性指数（SI）。在测试的 14 种分子中，有两种表现出显著的抗疟活性（IC（50）=0.95 和 1.3 μM）和低毒性（IC（50）> 100 或 125 μM），与两种参考药物：氯喹和强力霉素相当。构效关系表明，发挥最佳作用的分子支架是 6-硝基-2-（对甲苯磺酰甲基）-N-（3-取代苯基）-喹唑啉-4-胺。最后，对这些命中分子进行了针对两种其他原生动物利什曼原虫和刚地弓形虫的潜在作用研究，表明这些分子具有选择性的抗疟活性。
