(S)-3-azido-1-(2,3,5,6-tetrafluorophenoxy)butan-2-one | 1160741-89-8

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 英文名称: (S)-3-azido-1-(2,3,5,6-tetrafluorophenoxy)butan-2-one
• 英文别名: (3S)-3-azido-1-(2,3,5,6-tetrafluorophenoxy)butan-2-one
• CAS: 1160741-89-8
• 化学式: C₁₀H₇F₄N₃O₂
• 分子量: 277.178
• InChiKey: SDFNKQBSDUWCLV-BYPYZUCNSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  19
• 可旋转键数：
  5
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  40.7
• 氢给体数：
  0
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  、 (S)-3-azido-1-(2,3,5,6-tetrafluorophenoxy)butan-2-one 在 copper(II) sulfate 、 sodium ascorbate 作用下， 以 水 、 叔丁醇 为溶剂， 以43%的产率得到3-(4-((S)-3-methyl-2-(quinolin-6-ylmethylamino)butan-2-yl)-1H-1,2,3-triazol-1-yl)-1-(2,3,5,6-tetrafluorophenoxy)butan-2-one
  参考文献：
  名称：

  Nonpeptidic Tetrafluorophenoxymethyl Ketone Cruzain Inhibitors as Promising New Leads for Chagas Disease Chemotherapy

  摘要：

  A century after discovering that file Trypanosoma cruzi parasite is the etiological agent of Chagas disease, treatment is still plagued by limited efficacy, toxicity, and the emergence of drug, resistance. The development of inhibitors of the major T. cruzi cysteine protease, cruzain, has been demonstrated to be a promising drug discovery avenue for this neglected disease. Here we establish that a nonpeptidic tetrafluorophenoxymethyl ketone cruzain inhibitor Substantially ameliorates symptoms of acute Chagas disease in a mouse model With no apparent toxicity. A high-resolution Crystal Structure confirmed the mode of inhibition and revealed key binding interactions of this novel inhibitor class. Subsequent structure-guided optimization then resulted in inhibitor analogues With improvements in potency despite minimal or no additions in molecular weight. Evaluation Of file analogues in cell Culture showed enhanced activity. These results suggest that nonpeptidic tetrafluorophenoxymethyl ketone cruzain inhibitors have the Potential to fulfill file Urgent need for improved Chagas disease chemotherapy.

  DOI：

  10.1021/jm901633v
• 作为产物：
  描述：

  2,3,5,6-四氟苯酚 、 3-azido-1-bromobutan-2-one 在 potassium fluoride 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 3.17h， 以0.125 g的产率得到(S)-3-azido-1-(2,3,5,6-tetrafluorophenoxy)butan-2-one
  参考文献：
  名称：

  Nonpeptidic Tetrafluorophenoxymethyl Ketone Cruzain Inhibitors as Promising New Leads for Chagas Disease Chemotherapy

  摘要：

  A century after discovering that file Trypanosoma cruzi parasite is the etiological agent of Chagas disease, treatment is still plagued by limited efficacy, toxicity, and the emergence of drug, resistance. The development of inhibitors of the major T. cruzi cysteine protease, cruzain, has been demonstrated to be a promising drug discovery avenue for this neglected disease. Here we establish that a nonpeptidic tetrafluorophenoxymethyl ketone cruzain inhibitor Substantially ameliorates symptoms of acute Chagas disease in a mouse model With no apparent toxicity. A high-resolution Crystal Structure confirmed the mode of inhibition and revealed key binding interactions of this novel inhibitor class. Subsequent structure-guided optimization then resulted in inhibitor analogues With improvements in potency despite minimal or no additions in molecular weight. Evaluation Of file analogues in cell Culture showed enhanced activity. These results suggest that nonpeptidic tetrafluorophenoxymethyl ketone cruzain inhibitors have the Potential to fulfill file Urgent need for improved Chagas disease chemotherapy.

  DOI：

  10.1021/jm901633v

文献信息

• [EN] NONPEPTIDIC INHIBITORS OF CRUZAIN<br/>[FR] INHIBITEURS NON PEPTIDIQUES DE LA CRUAZÏNE
  申请人：UNIV CALIFORNIA

  公开号：WO2009075778A2

  公开（公告）日：2009-06-18

  Cruzain is the major cysteine protease of T. cruzi, which is the causative agent of Chagas' disease and is a promising target for the development of new chemotherapy. With the goal of developing potent nonpeptidic inhibitors of cruzain, the Substrate Activity Screening (SAS) method was used to screen a library of protease substrates initially designed to target the homologous human protease cathepsin S. Structure-based design was next used to further improve substrate cleavage efficiency by introducing additional binding interactions in the S3 pocket of cruzain. The optimized substrates were then converted to inhibitors by the introduction of cysteine protease mechanism-based pharmacophores. Inhibitor (38) was determined to be reversible even though it incorporated the vinyl sulfone pharmacophore that is well documented to give irreversible cruzain inhibition for peptidic inhibitors. The previously unexplored β-chloro vinyl sulfone pharmacophore provided mechanistic insight that led to the development of potent irreversible acyl- and aryl- oxymethyl ketone cruzain inhibitors. For these inhibitors, potency did not solely depend on leaving group pTa, with 2,3,5,6-tetrafluorophenoxy methyl ketone (54) identified as one of the most potent inhibitors with a second order inactivation constant of 147,000 s-1M-1. This inhibitor completely eradicated the T. cruzi parasite from mammalian cell cultures and consequently has the potential to lead to new chemo therapeutics for Chagas' disease.