De D, Krogstad F M, Cogswell F B, Krogstad D J
Department of Tropical Medicine, Tulane University, New Orleans, Louisiana, USA.
Am J Trop Med Hyg. 1996 Dec;55(6):579-83. doi: 10.4269/ajtmh.1996.55.579.
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 [IC50s] = 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.
氨基喹啉（AQ）耐药性是导致恶性疟原虫引起的疟疾在全球范围内再度流行的最重要因素之一。我们合成了一系列氨基喹啉，以确定其对氯喹敏感及耐药的恶性疟原虫发挥作用的构效关系。带有乙基、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氨基喹啉对氯喹敏感的恶性疟原虫具有同等活性（50%抑制浓度[IC50s]=5-15 nM）。带有乙基、丙基、异丙基、癸基或十二烷基侧链的氨基喹啉对氯喹、甲氟喹和多重耐药的恶性疟原虫也具有活性（IC50s=5-20 nM）。维拉帕米可增强氯喹对氯喹耐药寄生虫的活性，但对那些对耐药寄生虫具有活性的氨基喹啉的活性没有影响。这些结果表明，带有2-12个碳侧链的氨基喹啉对氯喹敏感的恶性疟原虫的活性与氯喹相当，并且带有比氯喹侧链短或长的氨基喹啉通常对氯喹、甲氟喹和多重耐药的恶性疟原虫具有活性。
