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首页> 外文期刊>Journal of Medicinal Chemistry >Methyl-substituted dispiro-1,2,4,5-tetraoxanes: correlations of structural studies with antimalarial activity.
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Methyl-substituted dispiro-1,2,4,5-tetraoxanes: correlations of structural studies with antimalarial activity.

机译：甲基取代的二螺-1,2,4,5-四恶烷：结构研究与抗疟活性的相关性。

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摘要

Two tetramethyl-substituted dispiro-1,2,4,5-tetraoxanes (7,8,15, 16-tetraoxadispiro[5.2.5.2]hexadecanes) 3 and 4 were designed as metabolically stable analogues of the dimethyl-substituted dispiro-1, 2,4,5-tetraoxane prototype WR 148999 (2). For a positive control we selected the sterically unhindered tetraoxane 5 (7,8,15, 16-tetraoxadispiro[5.2.5.2]hexadecane), devoid of any substituents. Tetraoxanes 3 and 4 were completely inactive in contrast to tetraoxanes 2 and 5. We hypothesize that the two inactive tetraoxanes possess sufficient steric hindrance about the tetraoxane ring due to the two additional axial methyl groups to prevent their activation to presumed parasiticidal carbon radicals by inhibiting electron transfer from heme or other iron(II) species. For each of the tetraoxanes 2-4, the tetraoxane and both spirocyclohexyl rings are in a chair conformation and the bond lengths and angles are all quite normal except for the C1-C2 bond which is slightly lengthened. Comparison of the modeled and X-ray structures for tetraoxanes 2-5 reveals that molecular mechanics (MMX and MM3) and 3-21G calculations each gave accurate structural parameters such as bond lengths, bond angles, and dihedral angles. In contrast, semiempirical methods such as AM1 gave poor results.
机译：设计了两个四甲基取代的二螺-1,2,4,5-四恶烷（7,8,15，16-四恶二螺[5.2.5.2]十六烷）3和4作为二甲基取代的dispiro-1的代谢稳定类似物， 2,4,5-四恶烷原型WR 148999（2）。对于阳性对照，我们选择没有任何取代基的空间不受阻的四恶烷5（7,8,15，16-四恶二螺[5.2.5.2]十六烷）。与四恶烷2和5相比，四恶烷3和4完全是惰性的。我们假设这两个无活性的四恶烷在四恶烷环上具有足够的空间位阻，这是由于另外两个轴向甲基阻止了它们通过抑制电子而活化为假定的杀寄生性碳自由基从血红素或其他铁（II）物种转移。对于每个四恶烷2-4，四恶烷和两个螺环己基环均处于椅子构象，并且键的长度和角度都非常正常，除了C1-C2键略微延长。对四恶烷2-5的建模结构和X射线结构的比较表明，分子力学（MMX和MM3）和3-21G计算分别给出了准确的结构参数，例如键长，键角和二面角。相比之下，半经验方法（例如AM1）的结果较差。

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