2-(4-hydroxyphenyl)-3-(prop-2-yn-1-yl)quinazolin-4(3H)-one | 1427578-96-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: 2-(4-hydroxyphenyl)-3-(prop-2-yn-1-yl)quinazolin-4(3H)-one
• 英文别名: 2-(4-Hydroxyphenyl)-3-prop-2-ynylquinazolin-4-one
• CAS: 1427578-96-8
• 化学式: C₁₇H₁₂N₂O₂
• 分子量: 276.294
• InChiKey: PINNSZJCSHDVLO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  21
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.06
• 拓扑面积：
  52.9
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  2-(4-hydroxyphenyl)-3-(prop-2-yn-1-yl)quinazolin-4(3H)-one 在 五甲基环戊二烯基双(三苯基膦)氯化钌(II) 、 三甲基铵三氧化硫共聚物 、 三乙胺 作用下， 以 1,4-二氧六环 、 乙腈 为溶剂， 反应 12.5h， 生成
  参考文献：
  名称：

  通过变构，硫酸化的小分子调节血浆。

  摘要：

  纤溶酶是一种关键的丝氨酸蛋白酶，在血块溶解和细胞外基质重塑中起主要作用。肝素是一种天然的多分散的硫酸化糖胺聚糖，已知会变构地调节纤溶酶的活性。迄今为止，尚未发现纤溶酶的变构抑制剂。我们基于9个不同的支架以及不同数量和位置的硫酸盐基团，筛选了55个硫酸化的小糖胺聚糖模拟物的内部库，以发现一些有前途的命中。其中，发现五硫酸化的类黄酮-喹唑啉酮二聚体32是最有效的硫酸化纤溶酶小抑制剂（IC50 = 45μM，功效= 100％）。Michaelis-Menten动力学研究表明，这些抑制剂对纤溶酶具有变构抑制作用。研究还表明，最有效的抑制剂对纤溶酶的选择性优于凝血酶和Xa因子，两种丝氨酸蛋白酶在凝血级联反应中 有趣的是，不同的抑制剂表现出不同的功效水平（40％-100％），这一观察结果暗示了变构过程提供的独特优势。总体而言，我们的工作提出了首个小型的合成别构纤溶酶抑制剂，用于进一步的合理设计。

  DOI：

  10.3390/molecules20010608
• 作为产物：
  描述：

  2-(4-hydroxyphenyl)-4(3H)-quinazolinone 在 吡啶 、 lithium hydroxide monohydrate 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 2.0h， 生成 2-(4-hydroxyphenyl)-3-(prop-2-yn-1-yl)quinazolin-4(3H)-one
  参考文献：
  名称：

  通过变构，硫酸化的小分子调节血浆。

  摘要：

  纤溶酶是一种关键的丝氨酸蛋白酶，在血块溶解和细胞外基质重塑中起主要作用。肝素是一种天然的多分散的硫酸化糖胺聚糖，已知会变构地调节纤溶酶的活性。迄今为止，尚未发现纤溶酶的变构抑制剂。我们基于9个不同的支架以及不同数量和位置的硫酸盐基团，筛选了55个硫酸化的小糖胺聚糖模拟物的内部库，以发现一些有前途的命中。其中，发现五硫酸化的类黄酮-喹唑啉酮二聚体32是最有效的硫酸化纤溶酶小抑制剂（IC50 = 45μM，功效= 100％）。Michaelis-Menten动力学研究表明，这些抑制剂对纤溶酶具有变构抑制作用。研究还表明，最有效的抑制剂对纤溶酶的选择性优于凝血酶和Xa因子，两种丝氨酸蛋白酶在凝血级联反应中 有趣的是，不同的抑制剂表现出不同的功效水平（40％-100％），这一观察结果暗示了变构过程提供的独特优势。总体而言，我们的工作提出了首个小型的合成别构纤溶酶抑制剂，用于进一步的合理设计。

  DOI：

  10.3390/molecules20010608

文献信息

• [EN] ALLOSTERIC MODULATORS OF FACTOR XIa AS ANTICOAGULANT AGENTS<br/>[FR] MODULATEURS ALLOSTÉRIQUES DE FACTEUR XIA EN TANT QU'AGENTS ANTICOAGULANTS
  申请人：UNIV VIRGINIA COMMONWEALTH

  公开号：WO2014075045A1

  公开（公告）日：2014-05-15

  Compounds which allosterically modulate and/or inhibit factor XIa activity are provided, as are methods of their use. These compounds include i) sulfated gallolyl glucosides, ii) sulfated quinazolinones, and iii) sulfated inositol analogs. The compounds used as anticoagulant agents.

  提供了能够以别构调节和/或抑制XIa因子活性的化合物，以及它们的使用方法。这些化合物包括i) 硫酸酯化没食子醇葡萄糖苷，ii) 硫酸酯化喹唑啉酮，和iii) 硫酸酯化肌醇类似物。这些化合物被用作抗凝剂。
• Studies on fragment-based design of allosteric inhibitors of human factor XIa
  作者：Rio S. Boothello、Nehru Viji Sankaranarayanan、Daniel K. Afosah、Rajesh Karuturi、Rami A. Al-Horani、Umesh R. Desai

  DOI：10.1016/j.bmc.2020.115762

  日期：2020.12

  Human factor XIa (hFXIa) has emerged as an attractive target for development of new anticoagulants that promise higher level of safety. Different strategies have been adopted so far for the design of anti-hFXIa molecules including competitive and non-competitive inhibition. Of these, allosteric dysfunction of hFXIa's active site is especially promising because of the possibility of controlled reduction in activity that may offer a route to safer anticoagulants. In this work, we assess fragment-based design approach to realize a group of novel allosteric hFXIa inhibitors. Starting with our earlier discovery that sulfated quinazolinone (QAO) bind in the heparin-binding site of hFXIa, we developed a group of two dozen dimeric sulfated QAOs with intervening linkers that displayed a progressive variation in inhibition potency. In direct opposition to the traditional wisdom, increasing linker flexibility led to higher potency, which could be explained by computational studies. Sulfated QAO 19S was identified as the most potent and selective inhibitor of hFXIa. Enzyme inhibition studies revealed that 19S utilizes a non-competitive mechanism of action, which was supported by fluorescence studies showing a classic sigmoidal binding profile. Studies with selected mutants of hFXIa indicated that sulfated QAOs bind in heparin-binding site of the catalytic domain of hFXIa. Overall, the approach of fragment-based design offers considerable promise for designing heparin-binding site-directed allosteric inhibitors of hFXIa.
• Discovery of Allosteric Modulators of Factor XIa by Targeting Hydrophobic Domains Adjacent to Its Heparin-Binding Site
  作者：Rajesh Karuturi、Rami A. Al-Horani、Shrenik C. Mehta、David Gailani、Umesh R. Desai

  DOI：10.1021/jm301757v

  日期：2013.3.28

  To discover promising sulfated allosteric modulators (SAMs) of glycosaminoglycan-binding proteins (GBPs), such as human factor XIa (FXIa), we screened a library of 26 synthetic, sulfated quinazolin-4(3H)-ones (QAOs) resulting in the identification of six molecules that reduced the V-max of substrate hydrolysis without influencing the K-M. Mutagenesis of residues of the heparin-binding site (HBS) of FXIa introduced a nearly 5-fold loss in inhibition potency supporting recognition of an allosteric site. Fluorescence studies showed a sigmoidal binding profile indicating highly cooperative binding. Competition with a positively charged, heparin-binding polymer did not fully nullify inhibition suggesting importance of hydrophobic forces to binding. This discovery suggests the operation of a dual-element recognition process, which relies on an initial Coulombic attraction of anionic SAMs to the cationic HBS of FXIa that forms a locked complex through tight interaction with an adjacent hydrophobic patch. The dual-element strategy may be widely applicable for discovering SAMs of other GBPs.
• ALLOSTERIC MODULATORS OF FACTOR XIa AS ANTICOAGULANT AGENTS
  申请人：VIRGINIA COMMONWEALTH UNIVERSITY

  公开号：US20160311842A1

  公开（公告）日：2016-10-27

  Compounds which allosterically modulate and/or inhibit factor XIa activity are provided, as are methods of their use. These compounds include i) sulfated gallolyl glucosides, ii) sulfated quinazolinones, and iii) sulfated inositol analogs. The compounds used as anticoagulant agents.
• US9758459B2
  申请人：——

  公开号：US9758459B2

  公开（公告）日：2017-09-12