The crystal structure of halofantrine-ferriprotoporphyrin IX and the mechanism of action of arylmethanol antimalarials
The crystal structure of halofantrine-ferriprotoporphyrin IX and the mechanism of action of arylmethanol antimalarials
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DOI：
10.1016/j.jinorgbio.2008.04.001
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发表时间：
2008-08-01
影响因子：
3.9
通讯作者：
Egan, Timothy J.
中科院分区：
文献类型：
--
作者：
de Villiers, Katherine A.;Marques, Helder M.;Egan, Timothy J.
用单晶X射线衍射法测定了抗疟药卤泛群与铁原卟啉IX（Fe（III）PPIX）形成的配合物的晶体结构。该结构表明，卤泛群坐标的Fe（III）中心，通过其醇功能，除了π堆积菲环的卟啉。Fe（III）-O键的长度与醇盐而不是醇配位基团一致。铁卟啉是五配位的单体化合物。在乙腈溶液中加入卤泛群碱后Fe（III）PPIX的电子光谱变化与在相同溶剂中加入奎尼丁游离碱后观察到的变化几乎相同。这表明同源结合。基于这种同源性的奎尼丁、奎宁、9-表奎宁和9-表奎尼丁的Fe（III）PPIX络合物的分子力学建模表明，抗疟活性奎尼丁和奎宁可以容易地采用允许在质子化奎宁环叔氨基和未质子化血红素丙酸酯基团之间形成分子内盐桥的构象，而非活性差向异构体9-表奎尼丁和9-表奎宁必须采用高能构象以适应这种盐桥形成。我们建议，盐桥的形成可能会中断血红素解毒途径过程中形成的疟原虫色素前体二聚体的形成，因此占两个活性异构体的强活性。(c)2008年爱思唯尔公司All rights reserved.
The crystal structure of the complex formed between the antimalarial drug halofantrine and ferriprotoporphyrin IX (Fe(III)PPIX) has been determined by single crystal X-ray diffraction. The structure shows that halofantrine coordinates to the Fe(III) center through its alcohol functionality in addition to pi-stacking of the phenanthrene ring over the porphyrin. The length of the Fe(III)-O bond is consistent with an alkoxide and not an alcohol coordinating group. The iron porphyrin is five coordinate and monomeric. Changes in the electronic spectrum of Fe(III)PPIX upon addition of halofantrine base in acetonitrile solution are almost identical to those observed upon addition of quinidine free base in the same solvent. This suggests homologous binding. Molecular mechanics modeling of Fe(III)PPIX complexes of quinidine, quinine, 9-epiquinine and 9-epiquinidine based on this homology suggests that the antimalarially active quinidine and quinine can readily adopt conformations that permit formation of an intramolecular salt bridge between the protonated quinuclidine tertiary amino group and unprotonated heme propionate group, while the inactive epimers 9-epiquinidine and 9-epiquinine have to adopt high energy conformations in order to accommodate such salt bridge formation. We propose that salt bridge formation may interrupt formation of the hemozoin precursor dimer formed during the heme detoxification pathway and so account for the strong activity of the two active isomers. (c) 2008 Elsevier Inc. All rights reserved.