(S)-N-(1-cyanocyclopropyl)-3-(4-methoxyphenyl)-2-(((S)-2,2,2-trifluoro-1-(phenyl)ethyl)amino)propanamide

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (S)-N-(1-cyanocyclopropyl)-3-(4-methoxyphenyl)-2-(((S)-2,2,2-trifluoro-1-(phenyl)ethyl)amino)propanamide
• 英文别名: (S)-N-(1-cyanocyclopropyl)-3-phenyl-2-(((S)-2,2,2-trifluoro-1-(4-methoxyphenyl)ethyl)amino)propanamide
• 化学式: C₂₂H₂₂F₃N₃O₂
• 分子量: 417.4
• InChiKey: YAQFGUSAMGFXMD-OALUTQOASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  30
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  74.2
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  4-甲氧基-L-苯丙氨酸 在 sodium tetrahydroborate 、 氯化亚砜 、 potassium carbonate 、 N,N-二异丙基乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 四氢呋喃 、 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 46.0h， 生成 (S)-N-(1-cyanocyclopropyl)-3-(4-methoxyphenyl)-2-(((S)-2,2,2-trifluoro-1-(phenyl)ethyl)amino)propanamide 、 (S)-N-(1-cyanocyclopropyl)-3-phenyl-2-(((R)-2,2,2-trifluoro-1-(4-methoxyphenyl)ethyl)amino)propanamide
  参考文献：
  名称：

  非肽腈基半胱氨酸蛋白酶抑制剂的抗锥虫活性。

  摘要：

  半胱氨酸蛋白酶 cruzipain 被认为是恰加斯病治疗干预的有效靶点。基于已知与组织蛋白酶 K 抑制相关的两种支架，三种基于腈的半胱氨酸蛋白酶抑制剂在 0.1 μM 至 1 μM 范围内观察到针对克氏锥虫 CL Brener 菌株的抗锥虫活性。对锥虫显示出最大效力的两种化合物的 EC50 值（0.12 μM 和 0.25 μM）比在酶抑制测定中针对 cruzain（cruzipain 的重组形式）测得的相应 Ki 值低一个数量级。这意味着这两种化合物的抗锥虫活性可能不能仅通过抑制 cruzain 酶来解释，从而引发针对半胱氨酸蛋白酶的假定多药理学特征。

  DOI：

  10.1371/journal.pntd.0005343

文献信息

• Synthesis and structure-activity relationship of nitrile-based cruzain inhibitors incorporating a trifluoroethylamine-based P2 amide replacement
  作者：Juliana C. Gomes、Lorenzo Cianni、Jean Ribeiro、Fernanda dos Reis Rocho、Samelyn da Costa Martins Silva、Pedro Henrique Jatai Batista、Carolina Borsoi Moraes、Caio Haddad Franco、Lucio H.G. Freitas-Junior、Peter W. Kenny、Andrei Leitão、Antonio C.B. Burtoloso、Daniela de Vita、Carlos A. Montanari

  DOI：10.1016/j.bmc.2019.115083

  日期：2019.11

  The structure-activity relationship for nitrile-based cruzain inhibitors incorporating a P2 amide replacement based on trifluoroethylamine was explored by deconstruction of a published series of inhibitors. It was demonstrated that the P3 biphenyl substituent present in the published inhibitor structures could be truncated to phenyl with only a small loss of affinity. The effects of inverting the configuration of the P2 amide replacement and linking a benzyl substituent at P1 were observed to be strongly nonadditive. We show that plotting affinity against molecular size provides a means to visualize both the molecular size efficiency of structural transformations and the nonadditivity in the structure-activity relationship. We also show how the relationship between affinity and lipophilicity, measured by high-performance liquid chromatography with an immobilized artificial membrane stationary phase, may be used to normalize affinity with respect to lipophilicity.