Egan T J, Mavuso W W, Ross D C, Marques H M
Department of Chemistry, University of Cape Town, Rondebosch, South Africa.
J Inorg Biochem. 1997 Nov 1;68(2):137-45. doi: 10.1016/s0162-0134(97)00086-x.
The interaction of a variety of quinoline antimalarial drugs as well as other quinoline derivatives with strictly monomeric ferriprotoporphyrin IX [Fe(III)PPIX] has been investigated in 40% aqueous DMSO solution. At an apparent pH of 7.5 and 25 degrees C, log K values for bonding are 5.52 +/- 0.03 (chloroquine), 5.39 +/- 0.04 (amodiaquine), 4.10 +/- 0.02 (quinine), 4.04 +/- 0.03 (9-epiquinine), and 3.90 +/- 0.08 (mefloquine). Primaquine, 8-hydroxyquinoline, 5-aminoquinoline, 6-aminoquinoline, 8-aminoquinoline, and quinoline exhibit no evidence of interaction with Fe(III)PPIX. The enthalpy and entropy changes for the interaction of quinolines with Fe(III)PPIX, as determined from the temperature dependence of the log K values, exhibit a compensation phenomenon that is suggestive of hydrophobic interaction. This is supported by the finding that the interactions of chloroquine and quinine with Fe(III)PPIX are weakened by increasing concentrations of acetonitrile. Interactions of chloroquine, quinine, and 9-epiquinine with Fe(III)PPIX are shown to remain strong at pH 5.6, the approximate pH of the food vacuole of the malaria parasite which is believed to be the locus of drug activity. Implications for the design of antimalarial drugs are briefly discussed.
在40%的二甲基亚砜水溶液中，研究了多种喹啉抗疟药物以及其他喹啉衍生物与严格意义上的单体高铁原卟啉IX [Fe(III)PPIX] 的相互作用。在表观pH值为7.5和25℃的条件下，结合的log K值分别为5.52±0.03（氯喹）、5.39±0.04（阿莫地喹）、4.10±0.02（奎宁）、4.04±0.03（9-表奎宁）和3.90±0.08（甲氟喹）。伯氨喹、8-羟基喹啉、5-氨基喹啉、6-氨基喹啉、8-氨基喹啉和喹啉均未显示出与Fe(III)PPIX相互作用的证据。根据log K值的温度依赖性确定的喹啉与Fe(III)PPIX相互作用的焓变和熵变呈现出一种补偿现象，这表明存在疏水相互作用。这一观点得到了以下发现的支持：随着乙腈浓度的增加，氯喹和奎宁与Fe(III)PPIX的相互作用减弱。氯喹、奎宁和9-表奎宁与Fe(III)PPIX的相互作用在pH 5.6时仍然很强，pH 5.6是疟原虫食物泡的近似pH值，据信食物泡是药物活性的作用位点。本文简要讨论了这些结果对抗疟药物设计的启示。
