5-[4-methoxy-3-[4-[4-(2H-tetrazol-5-yl)phenoxy]butoxy]phenyl]-4,4-dimethyl-2-propan-2-ylpyrazol-3-one | 1402938-63-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 5-[4-methoxy-3-[4-[4-(2H-tetrazol-5-yl)phenoxy]butoxy]phenyl]-4,4-dimethyl-2-propan-2-ylpyrazol-3-one
• CAS: 1402938-63-9
• 化学式: C₂₆H₃₂N₆O₄
• 分子量: 492.578
• InChiKey: LSMMVMRAIOYJHV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  36
• 可旋转键数：
  11
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  115
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  4-甲氧基-3-苯基甲氧基苯甲酰氯 在 sodium azide 、 palladium 10% on activated carbon 、 甲酸铵 、 sodium hydride 、 氯化铵 、 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 19.33h， 生成 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

文献信息

• Catechol Pyrazolinones as Trypanocidals: Fragment-Based Design, Synthesis, and Pharmacological Evaluation of Nanomolar Inhibitors of Trypanosomal Phosphodiesterase B1
  作者：Kristina M. Orrling、Chimed Jansen、Xuan Lan Vu、Vreni Balmer、Patrick Bregy、Anitha Shanmugham、Paul England、David Bailey、Paul Cos、Louis Maes、Emily Adams、Erika van den Bogaart、Eric Chatelain、Jean-Robert Ioset、Andrea van de Stolpe、Stèphanie Zorg、Johan Veerman、Thomas Seebeck、Geert Jan Sterk、Iwan J. P. de Esch、Rob Leurs

  DOI：10.1021/jm301059b

  日期：2012.10.25

  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.