Antitrypanosomal Activity of 1,2-Dihydroquinolin-6-ols and Their Ester Derivatives
Antitrypanosomal Activity of 1,2-Dihydroquinolin-6-ols and Their Ester Derivatives
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DOI：
10.1021/jm900723w
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发表时间：
2010-02-11
影响因子：
7.3
通讯作者：
Werbovetz, Karl A.
中科院分区：
文献类型：
--
作者：
Fotie, Jean;Kaiser, Marcel;Werbovetz, Karl A.
目前非洲锥虫病二期化疗效果不理想。以抗锥虫先导化合物1，2-二氢-2，2，4-三甲基喹啉-6-基3，5-二甲氧基苯甲酸酯（TDR 20364，1a）为基础，进行了合成优化研究，试图发现新的具有有效体内活性的杀锥虫剂。虽然6-醚衍生物的活性低于先导化合物，但几种N1-取代的衍生物显示出纳摩尔IC 50值。B.罗德西亚杆菌STIB 900，选择性指数高达> 18000。1-苄基-1，2-二氢-2，2，4-三甲基喹啉-6-基乙酸酯（10a）对这些寄生虫显示出0.014 μ M的IC 50值和1700的选择性指数。腹腔注射10a 50 mg/kg/d，连续4天，可延长T. B.布鲁氏菌STIB 795感染的小鼠（> 14天，未处理的对照组为7.75天）。T. B.在体外将布氏杆菌暴露于10 α，表明这些1，2-二氢喹啉衍生物的杀锥虫作用模式中存在氧化应激。
The current chemotherapy for second stage human African trypanosomiasis is unsatisfactory. A synthetic optimization study based on the lead antitrypanosomal compound 1,2-dihydro-2,2,4-trimethylquinolin-6-yl 3,5-dimethoxybenzoate (TDR20364, 1a) was undertaken in an attempt to discover new trypanocides with potent in vivo activity. While 6-ether derivatives were less active than the lead compound, several N1-substituted derivatives displayed nanomolar IC50 values against T. b. rhodesiense STIB900 in vitro, with selectivity indexes up to > 18000. 1-Benzyl-1, 2-dlhydro-2,2,4-trimethylquinolin-6-yl acetate (10a) displayed an IC50 value of 0.014 mu M against these parasites and a selectivity index or 1700. Intraperitoneal administration of 10a at 50 (mg/kg)/day for 4 days caused a promising prolongation of lifespan in T. b. brucei STIB795-infected mice (> 14 days vs 7.75 days for untreated controls). Reactive oxygen species were produced when T. b. brucei were exposed to 10a in vitro, implicating oxidative stress in the trypanocidal mode of action of these 1,2-dihydroquinoline derivatives.