3-[2-(3-chlorophenyl)acetyl]-6-hydroxymethyl-2-oxo-2H-1-benzopyran-2-one | 871569-77-6

• 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-[2-(3-chlorophenyl)acetyl]-6-hydroxymethyl-2-oxo-2H-1-benzopyran-2-one
• 英文别名: 3-[2-(3-Chlorophenyl)acetyl]-6-(hydroxymethyl)chromen-2-one
• CAS: 871569-77-6
• 化学式: C₁₈H₁₃ClO₄
• 分子量: 328.752
• InChiKey: NHSCGJQTRMTATD-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  23
• 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：
  63.6
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  3-[2-(3-chlorophenyl)acetyl]-6-hydroxymethyl-2-oxo-2H-1-benzopyran-2-one 在 四己基氯化铵 、 三苯基膦 、 2,3-二氯-5,6-二氰基-1,4-苯醌 作用下， 以 二氯甲烷 为溶剂， 以20%的产率得到6-(Chloromethyl)-3-[2-(3-chlorophenyl)acetyl]chromen-2-one
  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
• 作为产物：
  描述：

  (3-氯苯基)乙酰氯 在 吡啶 作用下， 以 二氯甲烷 为溶剂， 反应 4.0h， 生成 3-[2-(3-chlorophenyl)acetyl]-6-hydroxymethyl-2-oxo-2H-1-benzopyran-2-one
  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

• 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.