1-ethyl-3-(5-(pyridin-3-yl)-1H-benzo[d]imidazol-2-yl)urea | 445011-87-0

• 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: 1-ethyl-3-(5-(pyridin-3-yl)-1H-benzo[d]imidazol-2-yl)urea
• 英文别名: 3-ethyl-1-[5-(pyridin-3-yl)-1H-1,3-benzodiazol-2-yl]urea；1-ethyl-3-(6-pyridin-3-yl-1H-benzimidazol-2-yl)urea
• CAS: 445011-87-0
• 化学式: C₁₅H₁₅N₅O
• 分子量: 281.317
• InChiKey: KWSSMBHDMXPYIA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  21
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.13
• 拓扑面积：
  82.7
• 氢给体数：
  3
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  5-(pyridin-3-yl)-1H-benzo[d]imidazol-2-amine 、 异氰酸乙酯 以 四氢呋喃 为溶剂， 以25 mg的产率得到1-ethyl-3-(5-(pyridin-3-yl)-1H-benzo[d]imidazol-2-yl)urea
  参考文献：
  名称：

  具有强力抗菌活性的新型DNA促旋酶和拓扑异构酶IV双靶标苯并咪唑尿素抑制剂：通过明智地使用结构指导的设计和结构与活性之间的关系，实现智能设计和进化。

  摘要：

  为了克服影响所有目前使用的抗生素种类的细菌耐药性问题，发现具有新颖作用机制的新型抗菌剂是必要的。细菌DNA促旋酶和拓扑异构酶IV是氟喹诺酮类抗生素的特征明确的临床验证靶标，它们通过抑制催化亚基发挥其抗菌活性。通过与它们的ATP位点相互作用来抑制这些靶标在临床上不太成功。提出了一种新型的低分子量，与ATP位点结合的回旋酶和拓扑异构酶IV合成抑制剂的发现和表征。苯并咪唑脲是两种酶的双重靶向抑制剂，并且对引起医院和社区获得性感染的各种相关病原体具有有效的抗菌活性。描述了通过使用结构指导的设计，建模和结构-活性关系来发现和优化这种新型抗菌剂。提供了在两种啮齿动物感染模型中通过口服和静脉内给药的酶抑制，抗菌活性和体内功效的数据。

  DOI：

  10.1021/jm800318d

文献信息

• Discovery of New Benzothiazole-Based Inhibitors of Breakpoint Cluster Region-Abelson Kinase Including the T315I Mutant
  作者：Seunghee Hong、Jinhee Kim、Sun-Mi Yun、Hyunseung Lee、Yoonsu Park、Soon-Sun Hong、Sungwoo Hong

  DOI：10.1021/jm301891t

  日期：2013.5.9

  The existence of drug resistance caused by mutations in the break-point cluster region-Abelson tyrosine kinase (Bcr-Abl) kinase domain remains a clinical challenge due to limited effective treatment options for chronic myeloid leukemia (CML). Herein we report a novel series of benzothiazole-based inhibitors that are effective against wild-type and T315I mutant Bcr-Abl kinases. The original hit compound, nocodazole, was extensively modified through a structure-based drug design strategy, especially by varying the groups at the C2 and C6 positions of the scaffold. In addition, the introduction of water-solubilizing groups at the terminal ethyl group resulted in enhanced physicochemical properties and potency in cellular inhibition. Several compounds inhibited the kinase activity of both wild-type Bcr-Abl and the T315I mutant with IC50 values in the picomolar range and exhibited good antiproliferative effects on Ba/F3 cell lines transformed with either wild-type or T315I mutant Bcr-Abl.
• Discovery of Picomolar ABL Kinase Inhibitors Equipotent for Wild Type and T315I Mutant via Structure-Based de Novo Design
  作者：Hwangseo Park、Seunghee Hong、Jinhee Kim、Sungwoo Hong

  DOI：10.1021/ja311756u

  日期：2013.6.5

  Although the constitutively activated break-point cluster region-Abelson (ABL) tyrosine kinase is known to cause chronic myelogenous leukemia (CML), the prevalence of drug-resistant ABL mutants has made it difficult to develop effective anti-CML drugs. With the aim to identify new lead compounds for anti-CML drugs, we carried out a structure-based de novo design using the scoring function improved by implementing an accurate solvation free energy term. This approach led to the identification of ABL inhibitors equipotent for the wild type and the most drug-resistant T315I mutant of ABL at the picomolar level. Decomposition analysis of the binding free energy showed that a decrease in the desolvation cost for binding in the ATP-binding site could be as important as the strengthening of enzyme-inhibitor interaction to enhance the potency of an ABL inhibitor with structural modifications. A similar energetic feature was also observed in free energy perturbation (FEP) calculations. Consistent with the previous experimental and computational studies, the hydrogen bond interactions with the backbone groups of Met318 proved to be the most significant binding forces to stabilize the inhibitors in the ATP-binding sites of the wild type and T315I mutant. The results of molecular dynamics simulations indicated that the dynamic stabilities of the hydrogen bonds between the inhibitors and Met318 should also be considered in designing the potent common inhibitors of the wild-type and T315I mutant of ABL.
• BACTERIAL GYRASE INHIBITORS AND USES THEREOF
  申请人：VERTEX PHARMACEUTICALS INCORPORATED

  公开号：EP1341769B1

  公开（公告）日：2007-10-17
• US7414046B2
  申请人：——

  公开号：US7414046B2

  公开（公告）日：2008-08-19
• USRE40245E1
  申请人：——

  公开号：USRE40245E1

  公开（公告）日：2008-04-15