tert-butyl N-[(5S)-5-[[(2S)-2-[[4-[4-[[(2S,3S)-1-[[(3S,4S)-1-(butylamino)-3-hydroxy-6-methyl-1-oxoheptan-4-yl]amino]-3-methyl-1-oxopentan-2-yl]carbamoyl]phenoxy]benzoyl]amino]-4-methylpentanoyl]amino]-6-[4-[(6-methoxyquinolin-8-yl)amino]pentylamino]-6-oxohexyl]carbamate | 918797-27-0

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 肽模拟物
• 英文名称: tert-butyl N-[(5S)-5-[[(2S)-2-[[4-[4-[[(2S,3S)-1-[[(3S,4S)-1-(butylamino)-3-hydroxy-6-methyl-1-oxoheptan-4-yl]amino]-3-methyl-1-oxopentan-2-yl]carbamoyl]phenoxy]benzoyl]amino]-4-methylpentanoyl]amino]-6-[4-[(6-methoxyquinolin-8-yl)amino]pentylamino]-6-oxohexyl]carbamate
• CAS: 918797-27-0
• 化学式: C₆₄H₉₅N₉O₁₁
• 分子量: 1166.51
• InChiKey: BAFMARVIPPIEQR-FAIPCECKSA-N

物化性质

• 熔点：
  203 °C
• 沸点：
  1286.0±65.0 °C(Predicted)
• 密度：
  1.143±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  10
• 重原子数：
  84
• 可旋转键数：
  37
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  277
• 氢给体数：
  9
• 氢受体数：
  13

反应信息

• 作为反应物：
  描述：

  tert-butyl N-[(5S)-5-[[(2S)-2-[[4-[4-[[(2S,3S)-1-[[(3S,4S)-1-(butylamino)-3-hydroxy-6-methyl-1-oxoheptan-4-yl]amino]-3-methyl-1-oxopentan-2-yl]carbamoyl]phenoxy]benzoyl]amino]-4-methylpentanoyl]amino]-6-[4-[(6-methoxyquinolin-8-yl)amino]pentylamino]-6-oxohexyl]carbamate 在 三氟乙酸 作用下， 生成 N-((2S)-1-((2S)-6-amino-1-(4-(6-methoxyquinolin-8-ylamino)pentylamino)-1-oxohexan-2-ylamino)-4-methyl-1-oxopentan-2-yl)-4-(4-((2S,3S)-1-((3S,4S)-1-(butylamino)-3-hydroxy-6-methyl-1-oxoheptan-4-ylamino)-3-methyl-1-oxopentan-2-ylcarbamoyl)phenoxy)benzamide
  参考文献：
  名称：

  Plasmepsin II inhibition and antiplasmodial activity of Primaquine–Statine `double-drugs'

  摘要：

  Statine-based inhibitors of Plasmepsin II (PLMII) coupled with Primaquine have been designed using the 'double-drug' approach. The IC50 values for PLMII inhibition ranged from 0.59 to 400 nM and the best IC50 value for inhibition of Plasmodium falciparum growth in vitro was 0.4 muM, which represent a remarkable improvement compared to other statine-based PLMII inhibitors. (C) 2004 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2004.03.030
• 作为产物：
  描述：

  {(S)-5-((S)-2-benzyloxycarbonylamino-4-methylpentanoylamino)-5-[4-(6-methoxyquinolin-8-ylamino)pentylcarbamoyl]pentyl}carbamic acid tert-butyl ester 在 palladium on activated charcoal N-甲基吗啉 、 氢气 、 1-羟基苯并三唑 、 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 生成 tert-butyl N-[(5S)-5-[[(2S)-2-[[4-[4-[[(2S,3S)-1-[[(3S,4S)-1-(butylamino)-3-hydroxy-6-methyl-1-oxoheptan-4-yl]amino]-3-methyl-1-oxopentan-2-yl]carbamoyl]phenoxy]benzoyl]amino]-4-methylpentanoyl]amino]-6-[4-[(6-methoxyquinolin-8-yl)amino]pentylamino]-6-oxohexyl]carbamate
  参考文献：
  名称：

  High Antiplasmodial Activity of Novel Plasmepsins I and II Inhibitors

  摘要：

  The aim of this study was to develop new antiplasmodial compounds acting through distinct mechanisms during both the liver and the blood stages of the parasite life cycle. Compounds were designed on the basis of the "double-drug" approach: primaquine, which has been linked to statine-based inhibitors of plasmepsins (PLMs), the plasmodial aspartic proteases involved in degradation of hemeoglobin. The compounds were tested in vitro for anti-PLM I/PLM II activities and against chloroquine-sensitive (D10) and chloroquine-resistant (W2) strains of P. falciparum. An antiplasmodial activity (IC50) as low as 0.1 mu M was obtained, an excellent improvement in comparison with inhibitors previously reported (IC50 = 2 - 20 mu M). The killing activity was equally directed against both P. falciparum strains and was correlated to lipophilicity (calculated as ALogP), for all compounds but one (9). All compounds inhibited PLM I and PLM II in the nanomolar range (K-i = 1 - 700 nM). The most promising compounds (2, 6, 10) were not cytotoxic against human fibroblasts at 100 mu M and were highly selective for PLMs vs human cathepsin D.

  DOI：

  10.1021/jm061033d