Acetic acid N'-[(2R,3S,4S,5R)-6-(N'-acetyl-hydrazino)-2,5-bis-((E)-3-bromo-allyloxy)-6-oxo-3,4-bis-trimethylsilanyloxy-hexanoyl]-hydrazide | 866755-92-2

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: Acetic acid N'-[(2R,3S,4S,5R)-6-(N'-acetyl-hydrazino)-2,5-bis-((E)-3-bromo-allyloxy)-6-oxo-3,4-bis-trimethylsilanyloxy-hexanoyl]-hydrazide
• 英文别名: (2R,3S,4S,5R)-1-N',6-N'-diacetyl-2,5-bis[(E)-3-bromoprop-2-enoxy]-3,4-bis(trimethylsilyloxy)hexanedihydrazide
• CAS: 866755-92-2
• 化学式: C₂₂H₄₀Br₂N₄O₈Si₂
• 分子量: 704.561
• InChiKey: ZOGCXRBCZIJMET-ZIHHZLPQSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.35
• 重原子数：
  38
• 可旋转键数：
  15
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.64
• 拓扑面积：
  153
• 氢给体数：
  4
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  Acetic acid N'-[(2R,3S,4S,5R)-6-(N'-acetyl-hydrazino)-2,5-bis-((E)-3-bromo-allyloxy)-6-oxo-3,4-bis-trimethylsilanyloxy-hexanoyl]-hydrazide 在 potassium fluoride 、 伯吉斯试剂 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 反应 23.0h， 生成 (1R,2R,3R,4R)-1,4-Bis-((E)-3-bromo-allyloxy)-1,4-bis-(5-methyl-[1,3,4]oxadiazol-2-yl)-butane-2,3-diol
  参考文献：
  名称：

  Synthesis of Malarial Plasmepsin Inhibitors and Prediction of Binding Modes by Molecular Dynamics Simulations

  摘要：

  A series of inhibitors of the malarial aspartic proteases Plm I and II have been synthesized with L-mannitol as precursor. These inhibitors are characterized by either a diacylhydrazine or a five-membered oxadiazole ring replacing backbone amide functionalities. Molecular dynamics simulations were applied in the design process. The computationally predicted Plm II K-i values were generally in excellent agreement with the biological results. The diacylhydrazine was found to be superior over the oxadiazole as an amide bond replacement in the Plm I and II inhibitors studied. An extensive flexibility of the S2 ' pocket was captured by the simulations predicting the binding mode of the unsymmetrical inhibitors. Plm I and II inhibitors with single digit nanomolar K-i values devoid of inhibitory activity toward human Cat D were identified. One compound, lacking amide bonds, was found to be Plm IV selective and very potent, with a K-i value of 35 nM.

  DOI：

  10.1021/jm050463l
• 作为产物：
  描述：

  2,5-O-bis((2E)-3-bromo-2-propen-1-yl)-L-mannaro-1,4:3,6-di-γ-lactone 在 三乙胺 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 75.0h， 生成 Acetic acid N'-[(2R,3S,4S,5R)-6-(N'-acetyl-hydrazino)-2,5-bis-((E)-3-bromo-allyloxy)-6-oxo-3,4-bis-trimethylsilanyloxy-hexanoyl]-hydrazide
  参考文献：
  名称：

  Synthesis of Malarial Plasmepsin Inhibitors and Prediction of Binding Modes by Molecular Dynamics Simulations

  摘要：

  A series of inhibitors of the malarial aspartic proteases Plm I and II have been synthesized with L-mannitol as precursor. These inhibitors are characterized by either a diacylhydrazine or a five-membered oxadiazole ring replacing backbone amide functionalities. Molecular dynamics simulations were applied in the design process. The computationally predicted Plm II K-i values were generally in excellent agreement with the biological results. The diacylhydrazine was found to be superior over the oxadiazole as an amide bond replacement in the Plm I and II inhibitors studied. An extensive flexibility of the S2 ' pocket was captured by the simulations predicting the binding mode of the unsymmetrical inhibitors. Plm I and II inhibitors with single digit nanomolar K-i values devoid of inhibitory activity toward human Cat D were identified. One compound, lacking amide bonds, was found to be Plm IV selective and very potent, with a K-i value of 35 nM.

  DOI：

  10.1021/jm050463l

文献信息

• Synthesis of Malarial Plasmepsin Inhibitors and Prediction of Binding Modes by Molecular Dynamics Simulations
  作者：Karolina Ersmark、Martin Nervall、Elizabeth Hamelink、Linda K. Janka、Jose C. Clemente、Ben M. Dunn、Michael J. Blackman、Bertil Samuelsson、Johan Åqvist、Anders Hallberg

  DOI：10.1021/jm050463l

  日期：2005.9.1

  A series of inhibitors of the malarial aspartic proteases Plm I and II have been synthesized with L-mannitol as precursor. These inhibitors are characterized by either a diacylhydrazine or a five-membered oxadiazole ring replacing backbone amide functionalities. Molecular dynamics simulations were applied in the design process. The computationally predicted Plm II K-i values were generally in excellent agreement with the biological results. The diacylhydrazine was found to be superior over the oxadiazole as an amide bond replacement in the Plm I and II inhibitors studied. An extensive flexibility of the S2 ' pocket was captured by the simulations predicting the binding mode of the unsymmetrical inhibitors. Plm I and II inhibitors with single digit nanomolar K-i values devoid of inhibitory activity toward human Cat D were identified. One compound, lacking amide bonds, was found to be Plm IV selective and very potent, with a K-i value of 35 nM.