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首页> 外文期刊>Dalton transactions: An international journal of inorganic chemistry >Alkoxide coordination of iron(III) protoporphyrin IX by antimalarial quinoline methanols: a key interaction observed in the solid-state and solution
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Alkoxide coordination of iron(III) protoporphyrin IX by antimalarial quinoline methanols: a key interaction observed in the solid-state and solution

机译：抗疟疾喹啉甲醇对原卟啉IX的醇盐配位作用：固态和溶液中观察到的关键相互作用

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摘要

The quinoline methanol antimalarial drug mefloquine is a structural analogue of the Cinchona alkaloids, quinine and quinidine. We have elucidated the single crystal X-ray diffraction structure of the complexes formed between racemic erythro mefloquine and ferriprotoporphyrin IX (Fe(III) PPIX) and show that alkoxide coordination is a key interaction in the solid-state. Mass spectrometry confirms the existence of coordination complexes of quinine, quinidine and mefloquine to Fe(III) PPIX in acetonitrile. The length of the iron(III)-O bond in the quinine and quinidine complexes as determined by Extended X-ray Absorption Fine Structure (EXAFS) spectroscopy unequivocally confirms that coordination of the quinoline methanol compounds to Fe(III) PPIX occurs in non-aqueous aprotic solution via their benzylic alkoxide functional group. UV-visible spectrophotometric titrations of the low-spin bis-pyridyl-Fe(III) PPIX complex with each of the quinoline methanol compounds results in the displacement of a single pyridine molecule and subsequent formation of a six-coordinate pyridine-Fe(III) PPIX-drug complex. We propose that formation of the drug-Fe(III) PPIX coordination complexes is favoured in a non-aqueous environment, such as that found in lipid bodies or membranes in the malaria parasite, and that their existence may contribute to the mechanism of haemozoin inhibition or other toxicity effects that lead ultimately to parasite death. In either case, coordination is a key interaction to be considered in the design of novel antimalarial drug candidates.
机译：喹啉甲醇抗疟药甲氟喹是金鸡纳生物碱，奎宁和奎尼丁的结构类似物。我们已经阐明了外消旋赤型甲氟喹与亚铁原卟啉IX（Fe（III）PPIX）之间形成的配合物的单晶X射线衍射结构，并表明醇盐配位是固态的关键相互作用。质谱法证实了在乙腈中存在奎宁，奎尼丁和甲喹与Fe（III）PPIX的配位络合物。通过扩展X射线吸收精细结构（EXAFS）光谱法确定的奎宁和奎尼丁配合物中的铁（III）-O键的长度明确证实了在非苯酚中会发生喹啉甲醇化合物与Fe（III）PPIX的配位质子惰性水溶液通过它们的苄基醇盐官能团。低旋转双吡啶-Fe（III）PPIX配合物与每种喹啉甲醇化合物的紫外可见分光光度滴定导致单个吡啶分子的置换并随后形成六配位吡啶-Fe（III） PPIX-药物复合物。我们建议在非水环境中形成药物-Fe（III）PPIX配位化合物，例如在疟疾寄生虫的脂质体或膜中发现这种化合物，并且它们的存在可能有助于血红蛋白的抑制机制或最终导致寄生虫死亡的其他毒性作用。无论哪种情况，协调都是设计新型抗疟疾候选药物时要考虑的关键相互作用。

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