新型吲哚酮 N-氧化物衍生物的合成及抗疟活性。
Synthesis and antiplasmodial activity of new indolone N-oxide derivatives.
机构信息
Université de Toulouse, UPS, UMR 152 (Laboratoire de Pharmacochimie des Substances Naturelles et Pharmacophores Redox), F-31062 Toulouse cedex 9, France.
出版信息
J Med Chem. 2010 Jan 28;53(2):699-714. doi: 10.1021/jm901300d.
A series of 66 new indolone-N-oxide derivatives was synthesized with three different methods. Compounds were evaluated for in vitro activity against CQ-sensitive (3D7), CQ-resistant (FcB1), and CQ and pyrimethamine cross-resistant (K1) strains of Plasmodium falciparum (P.f.), as well as for cytotoxic concentration (CC(50)) on MCF7 and KB human tumor cell lines. Compound 26 (5-methoxy-indolone-N-oxide analogue) had the most potent antiplasmodial activity in vitro (<3 nM on FcB1 and = 1.7 nM on 3D7) with a very satisfactory selectivity index (CC(50) MCF7/IC(50) FcB1: 14623; CC(50) KB/IC(50) 3D7: 198823). In in vivo experiments, compound 1 (dioxymethylene derivatives of the indolone-N-oxide) showed the best antiplasmodial activity against Plasmodium berghei, 62% inhibition of the parasitaemia at 30 mg/kg/day.
合成了一系列 66 种新的吲哚啉-N-氧化物衍生物，采用了三种不同的方法。评估了这些化合物对体外敏感（3D7）、耐药（FcB1）和对氯喹和乙胺嘧啶交叉耐药（K1）的恶性疟原虫（Pf）株的活性，以及对 MCF7 和 KB 人肿瘤细胞系的细胞毒性浓度（CC（50））。化合物 26（5-甲氧基吲哚啉-N-氧化物类似物）具有最强的体外抗疟原虫活性（FcB1 上<3 nM，3D7 上=1.7 nM），具有非常令人满意的选择性指数（CC（50）MCF7/IC（50）FcB1：14623；CC（50）KB/IC（50）3D7：198823）。在体内实验中，化合物 1（吲哚啉-N-氧化物的二氧亚甲基衍生物）对疟原虫伯氏疟原虫显示出最好的抗疟原虫活性，每天 30mg/kg 可抑制 62%的寄生虫血症。
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