2,5-O-bis((2E)-3-bromo-2-propen-1-yl)-L-mannaro-1,4:3,6-di-γ-lactone | 652993-21-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 呋喃类
• 英文名称: 2,5-O-bis((2E)-3-bromo-2-propen-1-yl)-L-mannaro-1,4:3,6-di-γ-lactone
• 英文别名: (3R,3aR,6R,6aR)-3,6-bis[(E)-3-bromoprop-2-enoxy]-3,3a,6,6a-tetrahydrofuro[3,2-b]furan-2,5-dione
• CAS: 652993-21-0
• 化学式: C₁₂H₁₂Br₂O₆
• 分子量: 412.032
• InChiKey: FTGQFUHCRVUWRC-SKCAGLGNSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.42
• 重原子数：
  20.0
• 可旋转键数：
  6.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  71.06
• 氢给体数：
  0.0
• 氢受体数：
  6.0

反应信息

• 作为反应物：
  描述：

  2,5-O-bis((2E)-3-bromo-2-propen-1-yl)-L-mannaro-1,4:3,6-di-γ-lactone 在 2-羟基吡啶 作用下， 以 二氯甲烷 为溶剂， 反应 15.0h， 生成 (2R,3R,4R,5R)-2,5-bis[(E)-3-bromoprop-2-enoxy]-3,4-dihydroxy-N-[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]-6-oxo-6-[2-(2-phenylacetyl)hydrazinyl]hexanamide
  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：

  L-mannaro-1,4:3,6-di-γ-lactone 、 (2E)-3-bromo-2-propene-1-yl 2,2,2-trichloroethanimidate 在 三氟化硼乙醚 作用下， 以 1,4-二氧六环 为溶剂， 反应 1.5h， 以89%的产率得到2,5-O-bis((2E)-3-bromo-2-propen-1-yl)-L-mannaro-1,4:3,6-di-γ-lactone
  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