2-(3-cyclohexyl-3-methylthioureido)-4,5-dimethylthiophene-3-carboxylic acid | 207743-92-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 噻吩类
• 英文名称: 2-(3-cyclohexyl-3-methylthioureido)-4,5-dimethylthiophene-3-carboxylic acid
• 英文别名: 2-[[cyclohexyl(methyl)carbamothioyl]amino]-4,5-dimethylthiophene-3-carboxylic acid
• CAS: 207743-92-8
• 化学式: C₁₅H₂₂N₂O₂S₂
• 分子量: 326.484
• InChiKey: MEZMTOVQURDHAL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  21
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.6
• 拓扑面积：
  113
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  2-(3-cyclohexyl-3-methylthioureido)-4,5-dimethylthiophene-3-carboxylic acid 在 mercury(II) oxide 作用下， 以 二氯甲烷 为溶剂， 反应 48.0h， 以79%的产率得到2-[Cyclohexyl(methyl)amino]-5,6-dimethylthieno[2,3-d][1,3]oxazin-4-one
  参考文献：
  名称：

  Novel Thieno[2,3-d][1,3]oxazin-4-ones as Inhibitors of Human Leukocyte Elastase

  摘要：

  A series of thieno[2,3-d][1,3]oxazin-4-ones was synthesized and evaluated in vitro for inhibitory activity toward human leukocyte elastase. New synthetic routes to 2-alkoxy-, 2-alkylthio-, and 2-sec-amino-substituted derivatives are reported. This study demonstrates the versatility of 2-aminothiophenes prepared by Gewald reaction as a synthetic entry to serine protease-inhibiting, fused 1,3-oxazin-4-ones. Introduction of ethoxy, n-propoxy, and ethylthio groups at C-2 delivered the most potent inhibitors of this series with K-i values lower than 11 nM. Kinetic studies and product analyses revealed the formation of acyl-enzymes as a result of the attack of the active site serine at the carbon C-4 and subsequent deacylation. This mode of action is similar to the inhibition of serine proteases by 4H-3,1-benzoxazin-4-ones. Replacement of the benzene ring in benzoxazinones by a (substituted) thiophene led to improved hydrolytic stability and retained inhibitory potency.

  DOI：

  10.1021/jm9708341
• 作为产物：
  描述：

  N-甲基环己胺 在 sodium hydroxide 、 硫酸 作用下， 以 1,4-二氧六环 、 二氯甲烷 为溶剂， 反应 78.33h， 生成 2-(3-cyclohexyl-3-methylthioureido)-4,5-dimethylthiophene-3-carboxylic acid
  参考文献：
  名称：

  Novel Thieno[2,3-d][1,3]oxazin-4-ones as Inhibitors of Human Leukocyte Elastase

  摘要：

  A series of thieno[2,3-d][1,3]oxazin-4-ones was synthesized and evaluated in vitro for inhibitory activity toward human leukocyte elastase. New synthetic routes to 2-alkoxy-, 2-alkylthio-, and 2-sec-amino-substituted derivatives are reported. This study demonstrates the versatility of 2-aminothiophenes prepared by Gewald reaction as a synthetic entry to serine protease-inhibiting, fused 1,3-oxazin-4-ones. Introduction of ethoxy, n-propoxy, and ethylthio groups at C-2 delivered the most potent inhibitors of this series with K-i values lower than 11 nM. Kinetic studies and product analyses revealed the formation of acyl-enzymes as a result of the attack of the active site serine at the carbon C-4 and subsequent deacylation. This mode of action is similar to the inhibition of serine proteases by 4H-3,1-benzoxazin-4-ones. Replacement of the benzene ring in benzoxazinones by a (substituted) thiophene led to improved hydrolytic stability and retained inhibitory potency.

  DOI：

  10.1021/jm9708341

文献信息

• Aromatic 2-(Thio)ureidocarboxylic Acids As a New Family of Modulators of Multidrug Resistance-Associated Protein 1: Synthesis, Biological Evaluation, and Structure−Activity Relationships
  作者：Hans-Georg Häcker、Stefan Leyers、Jeanette Wiendlocha、Michael Gütschow、Michael Wiese

  DOI：10.1021/jm900688v

  日期：2009.8.13

  Four series of aromatic carboxylic acids were prepared with a urea or thiourea moiety at the neighboring position to the carboxyl group and benzene or thiophene as aromatic scaffold. Using a calcein AM assay, these compounds were evaluated as inhibitors of multidrug resistance-associated protein I (MRP1) and selected compounds were examined toward P-glycoprotein (P-gp) as well as breast cancer resistance protein (BCRP) to assess selectivity for MRP1. Two 2-thioureidobenzo[b]-thiophene-3-carboxylic acids (48, 49) were identified as particularly potent inhibitors of MRP1, with IC50 values of around 1 mu M. The structural features of this new family or nontoxic MRP1 inhibitors include a (thio)urea disubstituted with preferentially two alkyl groups at the terminal nitrogen and an additional fused aromatic ring.
• Novel Thieno[2,3-<i>d</i>][1,3]oxazin-4-ones as Inhibitors of Human Leukocyte Elastase
  作者：Michael Gütschow、Ulf Neumann

  DOI：10.1021/jm9708341

  日期：1998.5.1

  A series of thieno[2,3-d][1,3]oxazin-4-ones was synthesized and evaluated in vitro for inhibitory activity toward human leukocyte elastase. New synthetic routes to 2-alkoxy-, 2-alkylthio-, and 2-sec-amino-substituted derivatives are reported. This study demonstrates the versatility of 2-aminothiophenes prepared by Gewald reaction as a synthetic entry to serine protease-inhibiting, fused 1,3-oxazin-4-ones. Introduction of ethoxy, n-propoxy, and ethylthio groups at C-2 delivered the most potent inhibitors of this series with K-i values lower than 11 nM. Kinetic studies and product analyses revealed the formation of acyl-enzymes as a result of the attack of the active site serine at the carbon C-4 and subsequent deacylation. This mode of action is similar to the inhibition of serine proteases by 4H-3,1-benzoxazin-4-ones. Replacement of the benzene ring in benzoxazinones by a (substituted) thiophene led to improved hydrolytic stability and retained inhibitory potency.