Aminoquinolines that circumvent resistance in Plasmodium falciparum in vitro
Aminoquinolines that circumvent resistance in Plasmodium falciparum in vitro
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DOI：
10.4269/ajtmh.1996.55.579
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发表时间：
1996-12-01
影响因子：
3.3
通讯作者：
Krogstad, DJ
中科院分区：
文献类型：
--
作者：
De, DY;Krogstad, FM;Krogstad, DJ
氨基喹啉 (AQ) 耐药性是恶性疟原虫引起的疟疾在全球范围内卷土重来的最重要因素之一。我们合成了一系列 AQ 来定义 AQ 对氯喹敏感和耐药的恶性疟原虫发挥作用的构效关系。具有乙基、丙基、异丙基、丁基、戊基、异戊基（氯喹）、己基、辛基、癸基或十二烷基侧链的 AQ 对氯喹敏感的恶性疟原虫具有同等活性（50% 抑制浓度 [IC(50)s] = 5-15 nM）。具有乙基、丙基、异丙基、癸基或十二烷基侧链的 AQ 对氯喹、甲氟喹和多重耐药恶性疟原虫也具有活性 (IC50 = 5-20 nM)。维拉帕米可增强氯喹对抗氯喹抗性寄生虫的活性，但对对抗抗性寄生虫的 AQ 活性没有影响。这些结果表明，具有 2-12 个碳侧链的 AQ 对氯喹敏感的恶性疟原虫具有与氯喹一样的活性，并且侧链比氯喹短或长的 AQ 通常对氯喹、甲氟喹和多重抗性恶性疟有活性。
Aminoquinoline (AQ) resistance is one of the most important factors in the worldwide resurgence of malaria due to Plasmodium falciparum. We synthesized a series of AQs to define the structure-activity relationships responsible for AQ action against chloroquine-susceptible and -resistant P. falciparum. The AQs with ethyl, propyl, isopropyl, butyl, pentyl, isopentyl (chloroquine), hexyl, octyl, decyl, or dodecyl side chains were equally active against chloroquine-susceptible P. falciparum (50% inhibitory concentrations [IC(50)s] = 5-15 nM). The AQs with ethyl, propyl, isopropyl, decyl, or dodecyl side chains were also active against chloroquine-, mefloquine- and multiply-resistant P. falciparum (IC50s = 5-20 nM). Verapamil, which enhances the activity of chloroquine against chloroquine-resistant parasites, had no effect on the activity of AQs that were active against resistant parasites. These results indicate that AQs with 2-12 carbon side chains are as active as chloroquine against chloroquine-susceptible P. falciparum, and that AQs with side chains shorter or longer than chloroquine are often active against chloroquine-, mefloquine-, and multiply-resistant P. falciparum.