3-trifluoromethylphenyl 6-chloromethyl-2-oxo-2H-1-benzopyran-3-carboxylate | 217081-31-7

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 香豆素及其衍生物
• 英文名称: 3-trifluoromethylphenyl 6-chloromethyl-2-oxo-2H-1-benzopyran-3-carboxylate
• 英文别名: 6-Chloromethyl-2-oxo-2H-1-benzopyran-3-carboxylic acid 3-(trifluoromethyl)phenyl ester；[3-(trifluoromethyl)phenyl] 6-(chloromethyl)-2-oxochromene-3-carboxylate
• CAS: 217081-31-7
• 化学式: C₁₈H₁₀ClF₃O₄
• 分子量: 382.723
• InChiKey: GFWQRBXRVIMFMT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.8
• 重原子数：
  26
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.11
• 拓扑面积：
  52.6
• 氢给体数：
  0
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  2-羟基-5-(羟基甲基)苯甲醛 在 哌啶 、 吡啶 、 盐酸 、 氯化亚砜 、 溶剂黄146 作用下， 以 乙醇 为溶剂， 反应 25.0h， 生成 3-trifluoromethylphenyl 6-chloromethyl-2-oxo-2H-1-benzopyran-3-carboxylate
  参考文献：
  名称：

  3,6-Disubstituted Coumarins as Mechanism-Based Inhibitors of Thrombin and Factor Xa

  摘要：

  In this work, coumarins were screened on thrombin (THR) and factor Xa (FXa), two of the most promising targets for the development of anticoagulant drugs. This allowed us to highlight compound 30, characterized by a 2,5-dichlorophenyl ester in the 3-position and a chloromethyl moiety in the 6-position, as a very potent THR inhibitor (k(i)/K-I, = 37 000 M-1 s(-1)). Moreover, this compound exhibits good selectivity over FXa (168-fold) and trypsin (54-fold). The mechanism of inactivation was investigated in this series and significantly differs from that previously observed with (x-chymotrypsin. Indeed, the addition of hydrazine on the THR-inhibitor complex promotes a partial induced THR reactivation. This reactivation, confirmed by LC/MS, showed the resurgence of the native THR and a new dihydrazide complex. Docking experiments were then efficiently used to explain the trends observed in the enzymatic assays as well as to corroborate the postulated inhibition mechanism. Finally, the cell permeability of our derivatives was estimated using a computational approach.

  DOI：

  10.1021/jm050448g

文献信息

• Coumarinic derivatives as mechanism-based inhibitors of α-chymotrypsin and human leukocyte elastase
  作者：Lionel Pochet、Caroline Doucet、Georges Dive、Johan Wouters、Bernard Masereel、Michèle Reboud-Ravaux、Bernard Pirotte

  DOI：10.1016/s0968-0896(00)00071-7

  日期：2000.6

  inhibitory potency toward alpha-CT and HLE. Cycloalkyl esters and amides were found to be essentially inactive on both enzymes. On the opposite, aromatic esters strongly inactivated alpha-CT whereas HLE was less efficiently inhibited with dichlorophenyl ester derivatives (kinact/K(I) = 4000 M(-1) s(-1) for 36). Representative examples of amide, ester, thioester and ketone derivatives were prepared in order

  合成了新型香豆素衍生物，并测试了其对α-CT和HLE的抑制作用。发现环烷基酯和酰胺对两种酶基本上无活性。相反，芳香族酯强烈地使α-CT失活，而二氯苯基酯衍生物对HLE的抑制作用较弱（36的动力学/ K（I）= 4000 M（-1）s（-1））。制备酰胺，酯，硫代酯和酮衍生物的代表性实例，以评估香豆素环与苯基侧链之间的连接的影响。如修饰的胰凝乳蛋白酶的氨基酸分析所示，6-氯甲基衍生物不可逆地使α-CT失活是由于组氨酸残基的烷基化。相反，对HLE的抑制是短暂的。香豆素的内在反应性已使用配体与甲醇-水对之间的亲核反应模型进行了计算。从该计算看来，这些分子表达的抑制能力的差异不能仅通过内酯羰基对亲核攻击的反应性差异来解释。
• US6355658B1
  申请人：——

  公开号：US6355658B1

  公开（公告）日：2002-03-12
• 3,6-Disubstituted Coumarins as Mechanism-Based Inhibitors of Thrombin and Factor Xa
  作者：Raphaël Frédérick、Séverine Robert、Caroline Charlier、Jérôme de Ruyck、Johan Wouters、Bernard Pirotte、Bernard Masereel、Lionel Pochet

  DOI：10.1021/jm050448g

  日期：2005.12.1

  In this work, coumarins were screened on thrombin (THR) and factor Xa (FXa), two of the most promising targets for the development of anticoagulant drugs. This allowed us to highlight compound 30, characterized by a 2,5-dichlorophenyl ester in the 3-position and a chloromethyl moiety in the 6-position, as a very potent THR inhibitor (k(i)/K-I, = 37 000 M-1 s(-1)). Moreover, this compound exhibits good selectivity over FXa (168-fold) and trypsin (54-fold). The mechanism of inactivation was investigated in this series and significantly differs from that previously observed with (x-chymotrypsin. Indeed, the addition of hydrazine on the THR-inhibitor complex promotes a partial induced THR reactivation. This reactivation, confirmed by LC/MS, showed the resurgence of the native THR and a new dihydrazide complex. Docking experiments were then efficiently used to explain the trends observed in the enzymatic assays as well as to corroborate the postulated inhibition mechanism. Finally, the cell permeability of our derivatives was estimated using a computational approach.