4-[4-[5-(4,4-Dimethyl-5-oxo-1-propan-2-ylpyrazol-3-yl)-2-methoxyphenoxy]butoxy]benzonitrile | 1402938-62-8

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 4-[4-[5-(4,4-Dimethyl-5-oxo-1-propan-2-ylpyrazol-3-yl)-2-methoxyphenoxy]butoxy]benzonitrile
• 英文别名: 4-[4-[5-(4,4-dimethyl-5-oxo-1-propan-2-ylpyrazol-3-yl)-2-methoxyphenoxy]butoxy]benzonitrile
• CAS: 1402938-62-8
• 化学式: C₂₆H₃₁N₃O₄
• 分子量: 449.55
• InChiKey: QCLFOMANMRBJIN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.1
• 重原子数：
  33
• 可旋转键数：
  10
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  84.2
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  4-[4-[5-(4,4-Dimethyl-5-oxo-1-propan-2-ylpyrazol-3-yl)-2-methoxyphenoxy]butoxy]benzonitrile 在 sodium azide 、 氯化铵 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 1.0h， 以75%的产率得到5-[4-methoxy-3-[4-[4-(2H-tetrazol-5-yl)phenoxy]butoxy]phenyl]-4,4-dimethyl-2-propan-2-ylpyrazol-3-one
  参考文献：
  名称：

  Catechol Pyrazolinones as Trypanocidals: Fragment-Based Design, Synthesis, and Pharmacological Evaluation of Nanomolar Inhibitors of Trypanosomal Phosphodiesterase B1

  摘要：

  Trypanosomal phosphodiesterases B1 and B2 (TbrPDEB1 and TbrPDEB2) play an important role in the life cycle of Trypanosoma brucei, the causative parasite of human African trypanosomiasis (HAT), also known as African sleeping sickness. We used homology modeling and docking studies to guide fragment growing into the parasite-specific P-pocket in the enzyme binding site. The resulting catechol pyrazolinones act as potent TbrPDEB1 inhibitors with IC50 values down to 49 nM. The compounds also block parasite proliferation (e.g., VUF13525 (20b): T. brucei rhodesiense IC50 = 60 nM, T. brucei brucei IC50 = 520 nM, T. cruzi = 7.6 mu M), inducing a typical multiple nuclei and kinetoplast phenotype without being generally cytotoxic. The mode of action of 20b was investigated with recombinantly engineered trypanosomes expressing a cAMP-sensitive FRET sensor, confirming a dose-response related increase of intracellular cAMP levels in trypanosomes. Our findings further validate the TbrPDEB family as antitrypanosomal target.

  DOI：

  10.1021/jm301059b
• 作为产物：
  描述：

  4-甲氧基-3-苯基甲氧基苯甲酰氯 在 palladium 10% on activated carbon 、 甲酸铵 、 sodium hydride 、 一水合肼 、 lithium diisopropyl amide 作用下， 以 四氢呋喃 、 甲醇 、 乙醚 、 乙醇 、 正己烷 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 、 乙腈 、 mineral oil 为溶剂， 反应 18.33h， 生成 4-[4-[5-(4,4-Dimethyl-5-oxo-1-propan-2-ylpyrazol-3-yl)-2-methoxyphenoxy]butoxy]benzonitrile
  参考文献：
  名称：

  Catechol Pyrazolinones as Trypanocidals: Fragment-Based Design, Synthesis, and Pharmacological Evaluation of Nanomolar Inhibitors of Trypanosomal Phosphodiesterase B1

  摘要：

  Trypanosomal phosphodiesterases B1 and B2 (TbrPDEB1 and TbrPDEB2) play an important role in the life cycle of Trypanosoma brucei, the causative parasite of human African trypanosomiasis (HAT), also known as African sleeping sickness. We used homology modeling and docking studies to guide fragment growing into the parasite-specific P-pocket in the enzyme binding site. The resulting catechol pyrazolinones act as potent TbrPDEB1 inhibitors with IC50 values down to 49 nM. The compounds also block parasite proliferation (e.g., VUF13525 (20b): T. brucei rhodesiense IC50 = 60 nM, T. brucei brucei IC50 = 520 nM, T. cruzi = 7.6 mu M), inducing a typical multiple nuclei and kinetoplast phenotype without being generally cytotoxic. The mode of action of 20b was investigated with recombinantly engineered trypanosomes expressing a cAMP-sensitive FRET sensor, confirming a dose-response related increase of intracellular cAMP levels in trypanosomes. Our findings further validate the TbrPDEB family as antitrypanosomal target.

  DOI：

  10.1021/jm301059b