Integral Role of Water in the Solid-State Behavior of the Antileishmanial Drug Miltefosine.
Integral Role of Water in the Solid-State Behavior of the Antileishmanial Drug Miltefosine.
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DOI：
10.1021/acs.cgd.2c00843
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发表时间：
2022-10-05
影响因子：
3.8
通讯作者：
Steed, Jonathan W.
中科院分区：
文献类型：
--
作者：
Hall, Amy V.;Gostick, Isobel E. F.;Yufit, Dmitry S.;Marchant, Gloria Y.;Kirubakaran, Preyanthiny;Madu, Shadrack J.;Li, Mingzhong;Steel, Patrick G.;Steed, Jonathan W.
米替福新是一种重新利用的抗癌药物，也是目前唯一被批准用于治疗被忽视的热带疾病利什曼病的口服药物。米替福辛具有吸湿性，必须在零下温度下储存。在这项工作中，我们报告了米替福辛一水合物和甲醇溶剂合物，以及 12 和 14 碳链类似物水合物和溶剂合物的 X 射线结构。这三种水合物都是同构的，并且是 Z′ = 2 的构象同构。水弥合了由叉指双层结构引起的磷酸胆碱头基之间的间隙。这两种甲醇溶剂化物也是相互同构的，头部基团采用更延伸的构象。同样，溶剂桥接了双层中头部基团之间的间隙。没有分离出无水形式的米替福辛或其类似物，脱水导致结晶度显着降低。这是由于氢键供体（以水或溶剂分子的形式）在两性离子结构的稳定性中发挥着不可或缺的作用。水或溶剂分子形式的氢键供体在抗利什曼病药物米替福辛的稳定性中发挥着关键作用。
Miltefosine is a repurposed anticancer drug and currently the only orally administered drug approved to treat the neglected tropical disease leishmaniasis. Miltefosine is hygroscopic and must be stored at subzero temperatures. In this work, we report the X-ray structures of miltefosine monohydrate and methanol solvate, along with 12- and 14-carbon chain analogue hydrates and a solvate. The three hydrates are all isostructural and are conformational isomorphs with Z′ = 2. Water bridges the gap between phosphocholine head groups caused by the interdigitated bilayer structure. The two methanol solvates are also mutually isostructural with the head groups adopting a more extended conformation. Again, the solvent bridges the gap between head groups in the bilayer. No anhydrous form of miltefosine or its analogues were isolated, with dehydration resulting in significantly reduced crystallinity. This arises as a result of the integral role that hydrogen-bond donors (in the form of water or solvent molecules) play in the stability of the zwitterionic structures. Hydrogen-bond donors in the form of water or solvent molecules play a key role in the stability of the antileishmaniasis drug miltefosine.
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影响因子：
3.4
作者：
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通讯作者：
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影响因子：
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通讯作者：
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