Effects of highly active novel artemisinin-chloroquinoline hybrid compounds on β-hematin formation, parasite morphology and endocytosis in Plasmodium falciparum
Effects of highly active novel artemisinin-chloroquinoline hybrid compounds on β-hematin formation, parasite morphology and endocytosis in Plasmodium falciparum
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DOI：
10.1016/j.bcp.2011.04.018
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发表时间：
2011-08-01
影响因子：
5.8
通讯作者：
Chibale, Kelly
中科院分区：
文献类型：
--
作者：
Feng, Tzu-Shean;Guantai, Eric M.;Chibale, Kelly
4-通过Ugi-四组分缩合反应，将氨基喹啉与青蒿素和1，4-萘醌衍生物进行杂交，并研究其生物活性。含青蒿素的化合物6a-c及其盐6c-柠檬酸盐是抗疟原虫试验中最具活性的目标化合物。然而，尽管在体外活性强，他们也显示对哺乳动物细胞系的细胞毒性，并具有较低的治疗指数比氯喹。用这些含青蒿素的杂合化合物处理的寄生虫的形态变化与添加青蒿素后观察到的那些相似。这些杂合化合物似乎与氯喹和青蒿素具有相同的作用机制：它们表现出有效的β-血红素抑制活性;它们引起寄生虫内血红蛋白积累的增加，其介于青蒿琥酯和氯喹观察到的增加之间;它们似乎还抑制内吞作用，如寄生虫中运输囊泡数量减少所示。没有观察到这些混合化合物与氯喹的交叉耐药性，尽管它们含有氯喹啉部分。因此，杂交策略似乎是从两类抗疟药中借用最好的。(C)2011 Elsevier Inc. All rights reserved.
4-Aminoquinolines were hybridized with artemisinin and 1,4-naphthoquinone derivatives via the Ugi-four-component condensation reaction, and their biological activities investigated. The artemisinin-containing compounds 6a-c and its salt 6c-citrate were the most active target compounds in the antiplasmodial assays. However, despite the potent in vitro activities, they also displayed cytotoxicity against a mammalian cell-line, and had lower therapeutic indices than chloroquine. Morphological changes in parasites treated with these artemisinin-containing hybrid compounds were similar to those observed after addition of artemisinin. These hybrid compounds appeared to share mechanism(s) of action with both chloroquine and artemisinin: they exhibited potent beta-hematin inhibitory activities; they caused an increase in accumulation of hemoglobin within the parasites that was intermediate between the increase observed with artesunate and chloroquine; and they also appeared to inhibit endocytosis as suggested by the decrease in the number of transport vesicles in the parasites. No cross-resistance with chloroquine was observed for these hybrid compounds, despite the fact that they contained the chloroquinoline moiety. The hybridization strategy therefore appeared to be borrowing the best from both classes of antimalarials. (C) 2011 Elsevier Inc. All rights reserved.