2'-(4,4'-(2-hydroxypropane-1,3-diyl)bis(oxy)bis(4,1-phenylene))bis(1H-benzimidazole-5-carboxylic acid) | 1391725-16-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并咪唑类
• 英文名称: 2'-(4,4'-(2-hydroxypropane-1,3-diyl)bis(oxy)bis(4,1-phenylene))bis(1H-benzimidazole-5-carboxylic acid)
• 英文别名: 2-[4-[3-[4-(6-carboxy-1H-benzimidazol-2-yl)phenoxy]-2-hydroxypropoxy]phenyl]-3H-benzimidazole-5-carboxylic acid
• CAS: 1391725-16-8
• 化学式: C₃₁H₂₄N₄O₇
• 分子量: 564.554
• InChiKey: GBODXIMEGJFLQT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  42
• 可旋转键数：
  10
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.1
• 拓扑面积：
  171
• 氢给体数：
  5
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  对羟基苯甲醛 在 sodium disulfite 、 potassium carbonate 作用下， 以 乙醇 、 水 为溶剂， 反应 8.25h， 生成 2'-(4,4'-(2-hydroxypropane-1,3-diyl)bis(oxy)bis(4,1-phenylene))bis(1H-benzimidazole-5-carboxylic acid)
  参考文献：
  名称：

  Fragment-Based Design of Symmetrical Bis-benzimidazoles as Selective Inhibitors of the Trimethoprim-Resistant, Type II R67 Dihydrofolate Reductase

  摘要：

  The continuously increasing use of trimethoprim as a common antibiotic for medical use and for prophylactic application in terrestrial and aquatic animal farming has increased its prevalence in the environment. This has been accompanied by increased drug resistance, generally in the form of alterations in the drug target, dihydrofolate reductase (DHFR). The most highly resistant variants of DHFR are known as type II DHFR, among which R67 DHFR is the most broadly studied variant. We report the first attempt at designing specific inhibitors to this emerging drug target by fragment-based design. The detection of inhibition in R67 DHFR was accompanied by parallel monitoring of the human DHFR, as an assessment of compound selectivity. By those means, small aromatic molecules of 150-250 g/mol (fragments) inhibiting R67 DHFR selectively in the low millimolar range were identified. More complex, symmetrical bis-benzimidazoles and a bis-carboxyphenyl were then assayed as fragment-based leads, which procured selective inhibition of the target in the low micromolar range (K-i = 2-4 mu M). The putative mode of inhibition is discussed according to molecular modeling supported by in vitro tests.

  DOI：

  10.1021/jm201645r

文献信息

• Fragment-Based Design of Symmetrical Bis-benzimidazoles as Selective Inhibitors of the Trimethoprim-Resistant, Type II R67 Dihydrofolate Reductase
  作者：Dominic Bastien、Maximilian C. C. J. C. Ebert、Delphine Forge、Jacynthe Toulouse、Natalia Kadnikova、Florent Perron、Annie Mayence、Tien L. Huang、Jean Jacques Vanden Eynde、Joelle N. Pelletier

  DOI：10.1021/jm201645r

  日期：2012.4.12

  The continuously increasing use of trimethoprim as a common antibiotic for medical use and for prophylactic application in terrestrial and aquatic animal farming has increased its prevalence in the environment. This has been accompanied by increased drug resistance, generally in the form of alterations in the drug target, dihydrofolate reductase (DHFR). The most highly resistant variants of DHFR are known as type II DHFR, among which R67 DHFR is the most broadly studied variant. We report the first attempt at designing specific inhibitors to this emerging drug target by fragment-based design. The detection of inhibition in R67 DHFR was accompanied by parallel monitoring of the human DHFR, as an assessment of compound selectivity. By those means, small aromatic molecules of 150-250 g/mol (fragments) inhibiting R67 DHFR selectively in the low millimolar range were identified. More complex, symmetrical bis-benzimidazoles and a bis-carboxyphenyl were then assayed as fragment-based leads, which procured selective inhibition of the target in the low micromolar range (K-i = 2-4 mu M). The putative mode of inhibition is discussed according to molecular modeling supported by in vitro tests.