5-hydroxy-6-methoxy-2-methyl-benzofuran-3-carboxylic acid ethyl ester | 100798-29-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并呋喃
• 英文名称: 5-hydroxy-6-methoxy-2-methyl-benzofuran-3-carboxylic acid ethyl ester
• 英文别名: 5-Hydroxy-6-methoxy-2-methyl-benzofuran-3-carbonsaeure-aethylester；Ethyl 5-hydroxy-6-methoxy-2-methyl-1-benzofuran-3-carboxylate
• CAS: 100798-29-6
• 化学式: C₁₃H₁₄O₅
• 分子量: 250.251
• InChiKey: FTCYGAGHLWTUQZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  18
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  68.9
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  5-hydroxy-6-methoxy-2-methyl-benzofuran-3-carboxylic acid ethyl ester 在 咪唑 、 potassium fluoride 、 N-溴代丁二酰亚胺(NBS) 、 caesium carbonate 、 溶剂黄146 作用下， 以 乙酸乙酯 、 N,N-二甲基甲酰胺 为溶剂， 反应 37.0h， 生成
  参考文献：
  名称：

  Rational Design of Potent, Small, Synthetic Allosteric Inhibitors of Thrombin

  摘要：

  Thrombin is a key enzyme targeted by the majority of current anticoagulants that are direct inhibitors. Allosteric inhibition of thrombin may. offer a major advantage of finely tuned regulation. We present here sulfated benzofurans as the first examples of potent, small allosteric inhibitors of thrombin. A sulfated benzofuran library of 15 sulfated monomers and 13 sulfated dimers with different charged, polar, and hydrophobic substituents was studied in this work. Synthesis of the sulfated benzofurans was achieved through a multiple step, highly branched strategy, which culminated with microwave-assisted chemical sulfation. Of the 28 potential inhibitors, 11 exhibited reasonable inhibition of human a.-thrombin at pH 7.4. Structure-activity relationship analysis indicated that sulfation at the 5-position of the benzofuran scaffold was essential for targeting thrombin. A tert-butyl 5-sulfated benzofuran derivative was found to be the most potent thrombin inhibitor with an IC50 of 7.3 mu M under physiologically relevant conditions. Michaelis-Menten studies showed an allosteric inhibition phenomenon. Plasma clotting assays indicate that the sulfated benzofurans prolong both the activated partial thromboplastin time and prothrombin time. Overall, this work puts forward sulfated benzofurans as the first small, synthetic molecules as powerful lead compounds for the design of a new class of allosteric inhibitors of thrombin.

  DOI：

  10.1021/jm2005767
• 作为产物：
  描述：

  乙酰乙酸乙酯 在 caesium carbonate 、 N,N-二异丙基乙胺 作用下， 以 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 25.08h， 生成 5-hydroxy-6-methoxy-2-methyl-benzofuran-3-carboxylic acid ethyl ester
  参考文献：
  名称：

  Designing Allosteric Regulators of Thrombin. Exosite 2 Features Multiple Subsites That Can Be Targeted by Sulfated Small Molecules for Inducing Inhibition

  摘要：

  We recently designed a group of novel exosite-2-directed sulfated, small, allosteric inhibitors of thrombin. To develop more potent inhibitors, monosulfated benzofuran tri- and tetrameric homologues of the parent designed dimers were synthesized in seven to eight steps and found to exhibit a wide range of potencies. Among these, trimer 9a was found to be nearly 10-fold more potent than the first generation molecules. Michaelis-Menten studies indicated an allosteric mechanism of inhibition. Competitive studies using a hirudin peptide (exosite 1 ligand) and unfractionated heparin, heparin octasaccharide, and gamma'-fibrinogen peptide (exosite 2 ligands) demonstrated exosite 2 recognition in a manner different from that of the parent dimers. Alanine scanning mutagenesis of 12 Arg/Lys residues of exosite 2 revealed a defect in 9a potency for Arg233Ala thrombin only confirming the major difference in site of recognition between the two structurally related sulfated benzofurans. The results suggest that multiple avenues are available within exosite 2 for inducing thrombin inhibition.

  DOI：

  10.1021/jm400369q

文献信息

• First steps in the direction of synthetic, allosteric, direct inhibitors of thrombin and factor Xa
  作者：Jenson Verghese、Aiye Liang、Preet Pal Singh Sidhu、Michael Hindle、Qibing Zhou、Umesh R. Desai

  DOI：10.1016/j.bmcl.2009.06.013

  日期：2009.8

  Designing non-saccharide functional mimics of heparin is a major challenge. In this work, a library of small, aromatic molecules based on the sulfated DHP scaffold was synthesized and screened against thrombin and factor Xa. The results reveal that (i) selected monomeric benzofuran derivatives inhibit the two enzymes, albeit weakly; (ii) the two enzymes recognize different structural features in the

  设计肝素的非糖类功能模拟物是一项重大挑战。在这项工作中，合成了一个基于硫酸化 DHP 支架的芳香小分子库，并针对凝血酶和 Xa 因子进行了筛选。结果表明：（ⅰ）选择的单体苯并呋喃衍生物抑制这两种酶，尽管弱; (ii) 这两种酶识别所研究的苯并呋喃中的不同结构特征，表明识别具有显着的选择性；(iii) 抑制机制是变构的。这些分子代表了两种酶的第一个变构小分子抑制剂。
• 431. Michael additions to methoxy-p-benzoquinone
  作者：J. A. D. Jeffreys

  DOI：10.1039/jr9590002153

  日期：——
• A small group of sulfated benzofurans induces steady-state submaximal inhibition of thrombin
  作者：Daniel K. Afosah、Stephen Verespy、Rami A. Al-Horani、Rio S. Boothello、Rajesh Karuturi、Umesh R. Desai

  DOI：10.1016/j.bmcl.2018.01.069

  日期：2018.4

  Despite the development of promising direct oral anticoagulants, which are all orthosteric inhibitors, a sizable number of patients suffer from bleeding complications. We have hypothesized that allosterism based on the heparin-binding exosites presents a major opportunity to induce sub-maximal inhibition of coagulation proteases, thereby avoiding/reducing bleeding risk. We present the design of a group of sulfated benzofuran dimers that display heparin-binding site-dependent partial allosteric inhibition of thrombin against fibrinogen (Delta Y = 55-75%), the first time that a small molecule (MW < 800) has been found to thwart macromolecular cleavage by a monomeric protease in a controlled manner. The work leads to the promising concept that it should be possible to develop allosteric inhibitors that reduce clotting, but do not completely eliminate it, thereby avoiding major bleeding complications that beset anti-coagulants today. (C) 2018 Elsevier Ltd. All rights reserved.
• Designing Allosteric Regulators of Thrombin. Exosite 2 Features Multiple Subsites That Can Be Targeted by Sulfated Small Molecules for Inducing Inhibition
  作者：Preetpal Singh Sidhu、May H. Abdel Aziz、Aurijit Sarkar、Akul Y. Mehta、Qibing Zhou、Umesh R. Desai

  DOI：10.1021/jm400369q

  日期：2013.6.27

  We recently designed a group of novel exosite-2-directed sulfated, small, allosteric inhibitors of thrombin. To develop more potent inhibitors, monosulfated benzofuran tri- and tetrameric homologues of the parent designed dimers were synthesized in seven to eight steps and found to exhibit a wide range of potencies. Among these, trimer 9a was found to be nearly 10-fold more potent than the first generation molecules. Michaelis-Menten studies indicated an allosteric mechanism of inhibition. Competitive studies using a hirudin peptide (exosite 1 ligand) and unfractionated heparin, heparin octasaccharide, and gamma'-fibrinogen peptide (exosite 2 ligands) demonstrated exosite 2 recognition in a manner different from that of the parent dimers. Alanine scanning mutagenesis of 12 Arg/Lys residues of exosite 2 revealed a defect in 9a potency for Arg233Ala thrombin only confirming the major difference in site of recognition between the two structurally related sulfated benzofurans. The results suggest that multiple avenues are available within exosite 2 for inducing thrombin inhibition.
• Rational Design of Potent, Small, Synthetic Allosteric Inhibitors of Thrombin
  作者：Preetpal Singh Sidhu、Aiye Liang、Akul Y. Mehta、May H. Abdel Aziz、Qibing Zhou、Umesh R. Desai

  DOI：10.1021/jm2005767

  日期：2011.8.11

  Thrombin is a key enzyme targeted by the majority of current anticoagulants that are direct inhibitors. Allosteric inhibition of thrombin may. offer a major advantage of finely tuned regulation. We present here sulfated benzofurans as the first examples of potent, small allosteric inhibitors of thrombin. A sulfated benzofuran library of 15 sulfated monomers and 13 sulfated dimers with different charged, polar, and hydrophobic substituents was studied in this work. Synthesis of the sulfated benzofurans was achieved through a multiple step, highly branched strategy, which culminated with microwave-assisted chemical sulfation. Of the 28 potential inhibitors, 11 exhibited reasonable inhibition of human a.-thrombin at pH 7.4. Structure-activity relationship analysis indicated that sulfation at the 5-position of the benzofuran scaffold was essential for targeting thrombin. A tert-butyl 5-sulfated benzofuran derivative was found to be the most potent thrombin inhibitor with an IC50 of 7.3 mu M under physiologically relevant conditions. Michaelis-Menten studies showed an allosteric inhibition phenomenon. Plasma clotting assays indicate that the sulfated benzofurans prolong both the activated partial thromboplastin time and prothrombin time. Overall, this work puts forward sulfated benzofurans as the first small, synthetic molecules as powerful lead compounds for the design of a new class of allosteric inhibitors of thrombin.