(2R,3R,4R,5R)-N1,N6-Bis[(1S,2R)-2-hydroxy-1-indanyl]-2,5-di(allyloxy)-3,4-dihydroxyhexane-1,6-diamide | 652992-86-4

• 分子结构分类: 有机化合物 - 苯类化合物 - 茚满类
• 英文名称: (2R,3R,4R,5R)-N1,N6-Bis[(1S,2R)-2-hydroxy-1-indanyl]-2,5-di(allyloxy)-3,4-dihydroxyhexane-1,6-diamide
• 英文别名: (2R,3R,4R,5R)-3,4-dihydroxy-N,N'-bis[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]-2,5-bis(prop-2-enoxy)hexanediamide
• CAS: 652992-86-4
• 化学式: C₃₀H₃₆N₂O₈
• 分子量: 552.624
• InChiKey: VFYYMZZPLBYLND-YNMRTIPJSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  40
• 可旋转键数：
  13
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  158
• 氢给体数：
  6
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  (2R,3R,4R,5R)-N1,N6-Bis[(1S,2R)-2-hydroxy-1-indanyl]-2,5-di(allyloxy)-3,4-dihydroxyhexane-1,6-diamide 在 lithium aluminium tetrahydride 作用下， 以 四氢呋喃 为溶剂， 反应 48.0h， 以9%的产率得到(2R,3R,4R,5S)-2,5-Bis-allyloxy-3,4-dihydroxy-6-((1S,2R)-2-hydroxy-indan-1-ylamino)-hexanoic acid ((1S,2R)-2-hydroxy-indan-1-yl)-amide
  参考文献：
  名称：

  Potent Inhibitors of the Plasmodium falciparum Enzymes Plasmepsin I and II Devoid of Cathepsin D Inhibitory Activity

  摘要：

  The hemoglobin-degrading aspartic proteases plasmepsin I (Plin I) and plasmepsin II (Plin II) of the malaria parasite Plasmodium falciparum have lately emerged as putative drug targets. A series of C-2-symmetric compounds encompassing the 1,2-dihydroxyethylene scaffold and a variety of elongated P1/P1' side chains were synthesized via microwave-assisted palladium-catalyzed coupling reactions. Binding affinity calculations with the linear interaction energy method and molecular dynamics simulations reproduced the experimental binding data obtained in a Plm II assay with very good accuracy. Bioactive conformations of the elongated P1/P1' chains were predicted and agreed essentially with a recent X-ray structure. The compounds exhibited picomolar to nanomolar inhibition constants for the plasmepsins and no measurable affinity to the human enzyme cathepsin D. Some of the compounds also demonstrated significant inhibition of parasite growth in cell culture. To the best of our knowledge, these plasmepsin inhibitors represent the most selective reported to date and constitute promising lead compounds for further optimization.

  DOI：

  10.1021/jm030933g
• 作为产物：
  描述：

  L-mannaro-1,4:3,6-di-γ-lactone 在 三氟化硼乙醚 作用下， 以 1,4-二氧六环 、 二氯甲烷 为溶剂， 反应 19.0h， 生成 (2R,3R,4R,5R)-N1,N6-Bis[(1S,2R)-2-hydroxy-1-indanyl]-2,5-di(allyloxy)-3,4-dihydroxyhexane-1,6-diamide
  参考文献：
  名称：

  C2-Symmetric inhibitors of Plasmodium falciparum plasmepsin II: synthesis and theoretical predictions

  摘要：

  A series of C-2-symmetric compounds with a mannitol-based scaffold has been investigated, both theoretically and experimentally, as Plm II inhibitors. Four different stereoisomers with either benzyloxy or allyloxy P1/P1' side chains were studied. Computational ranking of the binding affinities of the eight compounds was carried out using the linear interaction energy (LIE) method relying on a complex previously determined by crystallography. Within both series of isomers the theoretical binding energies were in agreement with the enzymatic measurements, illustrating the power of the LIE method for the prediction of ligand affinities prior to synthesis. The structural models of the enzyme-inhibitor complexes obtained from the MD simulations provided a basis for interpretation of further structure-activity relationships. Hence, the affinity of a structurally similar ligand, but with a different P2/P2' substituent was examined using the same procedure. The predicted improvement in binding constant agreed well with experimental results. (C) 2003 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(03)00339-0

文献信息

• C2-Symmetric inhibitors of Plasmodium falciparum plasmepsin II: synthesis and theoretical predictions
  作者：Karolina Ersmark、Isabella Feierberg、Sinisa Bjelic、Johan Hultén、Bertil Samuelsson、Johan Åqvist、Anders Hallberg

  DOI：10.1016/s0968-0896(03)00339-0

  日期：2003.8

  A series of C-2-symmetric compounds with a mannitol-based scaffold has been investigated, both theoretically and experimentally, as Plm II inhibitors. Four different stereoisomers with either benzyloxy or allyloxy P1/P1' side chains were studied. Computational ranking of the binding affinities of the eight compounds was carried out using the linear interaction energy (LIE) method relying on a complex previously determined by crystallography. Within both series of isomers the theoretical binding energies were in agreement with the enzymatic measurements, illustrating the power of the LIE method for the prediction of ligand affinities prior to synthesis. The structural models of the enzyme-inhibitor complexes obtained from the MD simulations provided a basis for interpretation of further structure-activity relationships. Hence, the affinity of a structurally similar ligand, but with a different P2/P2' substituent was examined using the same procedure. The predicted improvement in binding constant agreed well with experimental results. (C) 2003 Elsevier Ltd. All rights reserved.
• Potent Inhibitors of the <i>Plasmodium </i><i>f</i><i>alciparum</i> Enzymes Plasmepsin I and II Devoid of Cathepsin D Inhibitory Activity
  作者：Karolina Ersmark、Isabella Feierberg、Sinisa Bjelic、Elizabeth Hamelink、Fiona Hackett、Michael J. Blackman、Johan Hultén、Bertil Samuelsson、Johan Åqvist、Anders Hallberg

  DOI：10.1021/jm030933g

  日期：2004.1.1

  The hemoglobin-degrading aspartic proteases plasmepsin I (Plin I) and plasmepsin II (Plin II) of the malaria parasite Plasmodium falciparum have lately emerged as putative drug targets. A series of C-2-symmetric compounds encompassing the 1,2-dihydroxyethylene scaffold and a variety of elongated P1/P1' side chains were synthesized via microwave-assisted palladium-catalyzed coupling reactions. Binding affinity calculations with the linear interaction energy method and molecular dynamics simulations reproduced the experimental binding data obtained in a Plm II assay with very good accuracy. Bioactive conformations of the elongated P1/P1' chains were predicted and agreed essentially with a recent X-ray structure. The compounds exhibited picomolar to nanomolar inhibition constants for the plasmepsins and no measurable affinity to the human enzyme cathepsin D. Some of the compounds also demonstrated significant inhibition of parasite growth in cell culture. To the best of our knowledge, these plasmepsin inhibitors represent the most selective reported to date and constitute promising lead compounds for further optimization.