Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa.
Biochem Pharmacol. 2011 Aug 1;82(3):236-47. doi: 10.1016/j.bcp.2011.04.018. Epub 2011 May 8.
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 β-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.
4-氨基喹啉与青蒿素和 1,4-萘醌衍生物通过 Ugi-四组分缩合反应进行杂交，并对其生物活性进行了研究。含青蒿素的化合物 6a-c 及其盐 6c-柠檬酸盐是抗疟活性测定中最有效的目标化合物。然而，尽管它们具有很强的体外活性，但对哺乳动物细胞系也表现出细胞毒性，并且治疗指数低于氯喹。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加入青蒿素后观察到的变化相似。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：它们表现出很强的β-血红素抑制活性；它们导致寄生虫内血红蛋白的积累增加，介于青蒿琥酯和氯喹观察到的增加之间；并且它们还似乎抑制内吞作用，因为寄生虫内的运输小泡数量减少。尽管这些杂合化合物含有氯喹啉部分，但与氯喹没有交叉耐药性。因此，杂交策略似乎从两类抗疟药中汲取了最好的部分。
