Department of Chemistry, McGill University , Montreal, H3A OB8, Quebec, Canada.
Inorg Chem. 2017 Jul 17;56(14):7803-7810. doi: 10.1021/acs.inorgchem.7b00526. Epub 2017 Jun 26.
Solution NMR has been used in tandem with a diamagnetic non-iron heme model compound as a simple and effective tool to rapidly probe the structures of the bound complexes formed between the metalloporphyrin and antimalarial drugs from the 4-aminoquinoline, 4-methylenehydroxylquinoline, and 8-aminoquinoline subfamilies. The ability of gallium(III) protoporphyrin IX to mimic heme chemistry is exploited. The 4-aminoquinolines quinacrine and amodiaquine and two novel 3-halo chloroquine analogues are found to bind to the metalloporphyrin through hydrogen-bonding and stacking interactions, while halofantrine and the 4-methylenehydroxylquinolines, quinine and mefloquine bind through the alcohol group of the drug. In each case, detailed structural information is available from the NMR assessment. The mefloquine model is confirmed crystallographically. The 8-aminoquinoline primaquine does not interact strongly. These tools show promise for future applications in assessing antimalarials in preclinical development for heme-binding drug targets.
溶液 NMR 已与反磁性非铁血红素模型化合物联合使用，作为一种快速探测金属卟啉与来自 4-氨基喹啉、4-亚甲二氧基喹啉和 8-氨基喹啉亚家族的抗疟药物之间形成的结合物的结构的简单而有效的工具。利用三价镓原卟啉 IX 模拟血红素化学。发现 4-氨基喹啉类药物奎宁和阿莫地喹以及两种新型 3-卤代氯喹类似物通过氢键和堆积相互作用与金属卟啉结合，而卤泛群和 4-亚甲二氧基喹啉类药物奎宁和甲氟喹通过药物的醇基团结合。在每种情况下，都可以从 NMR 评估中获得详细的结构信息。甲氟喹模型已通过晶体学得到证实。8-氨基喹啉伯氨喹啉则没有强烈的相互作用。这些工具有望在评估临床前开发阶段的血红素结合药物靶标中的抗疟药物方面有未来的应用。
