ethyl (Z/E)-2-tert-butoxycarbamoyl-3-(4-fluorophenyl)acrylate | 919995-86-1

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 肉桂酸及其衍生物
• 英文名称: ethyl (Z/E)-2-tert-butoxycarbamoyl-3-(4-fluorophenyl)acrylate
• 英文别名: ethyl 3-(4-fluorophenyl)-2-[(2-methylpropan-2-yl)oxycarbamoyl]prop-2-enoate
• CAS: 919995-86-1
• 化学式: C₁₆H₂₀FNO₄
• 分子量: 309.338
• InChiKey: JPMHSAKBDRHBPW-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  22
• 可旋转键数：
  7
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  64.6
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  ethyl (Z/E)-2-tert-butoxycarbamoyl-3-(4-fluorophenyl)acrylate 在 potassium hydroxide 、 盐酸 作用下， 以 乙醇 、 水 为溶剂， 生成 (E)-2-tert-butoxycarbamoyl-3-(4-fluorophenyl)acrylic acid
  参考文献：
  名称：

  Structure–Activity Relationships and Blood Distribution of Antiplasmodial Aminopeptidase-1 Inhibitors

  摘要：

  Malaria is a severe infectious disease that causes between 655 000 and 1.2 million deaths annually. To overcome the resistance to current drugs, new biological targets are needed for drug development. Aminopeptidase M1 (PfAM1), a zinc metalloprotease, has been proposed as a new drug target to fight malaria. Herein, we disclosed the structure-activity relationships of a selective family of hydroxamate PfAM1 inhibitors based on the malonic template. In particular, we performed a "fluoro-scanning" around hit 1 that enlightened the key positions of the halogen for activity. The docking of the best inhibitor 2 is consistent with in vitro results. The stability of 2 was evaluated in microsomes, in plasma, and toward glutathione. The in vivo distribution study performed with the nanomolar hydroxamate inhibitor 2 (BDM14471) revealed that it reaches its site of action. However, it fails to kill the parasite at concentrations relevant to the enzymatic inhibitory potency, suggesting that killing the parasite remains a challenge for potent and druglike catalytic-site binding PfAM1 inhibitors. In all, this study provides important insights for the design of inhibitors of PfAM1 and the validity of this target.

  DOI：

  10.1021/jm301506h
• 作为产物：
  描述：

  对氟苯甲醛 、 N-tert-butoxymalonamic acid ethyl ester 在 哌啶 作用下， 以 乙醇 为溶剂， 反应 3.5h， 生成 ethyl (Z/E)-2-tert-butoxycarbamoyl-3-(4-fluorophenyl)acrylate
  参考文献：
  名称：

  Structure–Activity Relationships and Blood Distribution of Antiplasmodial Aminopeptidase-1 Inhibitors

  摘要：

  Malaria is a severe infectious disease that causes between 655 000 and 1.2 million deaths annually. To overcome the resistance to current drugs, new biological targets are needed for drug development. Aminopeptidase M1 (PfAM1), a zinc metalloprotease, has been proposed as a new drug target to fight malaria. Herein, we disclosed the structure-activity relationships of a selective family of hydroxamate PfAM1 inhibitors based on the malonic template. In particular, we performed a "fluoro-scanning" around hit 1 that enlightened the key positions of the halogen for activity. The docking of the best inhibitor 2 is consistent with in vitro results. The stability of 2 was evaluated in microsomes, in plasma, and toward glutathione. The in vivo distribution study performed with the nanomolar hydroxamate inhibitor 2 (BDM14471) revealed that it reaches its site of action. However, it fails to kill the parasite at concentrations relevant to the enzymatic inhibitory potency, suggesting that killing the parasite remains a challenge for potent and druglike catalytic-site binding PfAM1 inhibitors. In all, this study provides important insights for the design of inhibitors of PfAM1 and the validity of this target.

  DOI：

  10.1021/jm301506h