chloride of 6-chloromethyl-2-oxo-2H-1-benzopyran-3-carboxylic acid | 176770-19-7

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 香豆素及其衍生物
• 英文名称: chloride of 6-chloromethyl-2-oxo-2H-1-benzopyran-3-carboxylic acid
• 英文别名: 6-hydroxymethyl-2-oxo-2H-chromene-3-carboxylic acid chloride；6-chloromethyl-2-oxo-2H-1-benzopyran-3-carboxylic acid chloride；6-(chloromethyl)-2-oxo-2H-1-benzopyran-3-carbonyl chloride；6-(Chloromethyl)-2-oxochromene-3-carbonyl chloride
• CAS: 176770-19-7
• 化学式: C₁₁H₆Cl₂O₃
• 分子量: 257.073
• InChiKey: ZQSRXVRQVDIRPF-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  16
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.09
• 拓扑面积：
  43.4
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  chloride of 6-chloromethyl-2-oxo-2H-1-benzopyran-3-carboxylic acid 在 吡啶 、 三氟乙酸 作用下， 以 1,4-二氧六环 、 二氯甲烷 为溶剂， 反应 2.17h， 生成 (2-Amino-5-chlorophenyl) 6-(chloromethyl)-2-oxochromene-3-carboxylate
  参考文献：
  名称：

  Mechanism-Based Thrombin Inhibitors:  Design, Synthesis, and Molecular Docking of a New Selective 2-Oxo-2H-1-benzopyran Derivative

  摘要：

  New 2-oxo-2H-1-benzopyran derivatives were prepared to optimize 2a,b, initially developed as mechanism-based alpha-chymotrypsin (alpha-CT) inhibitors, into potent and selective thrombin (THR) inhibitors. From this study, 22, characterized by a 2-(N-ethyl-2'-oxoacetamide)-5'-chlorophenyl ester side chain, was shown to be a good THR inhibitor (k(i)/K-I = 3455 M-1 center dot s(-1)), displaying an excellent selectivity profile against other serine proteases such as factor Xa, trypsin, and alpha-CT. Docking analysis of this compound into the different protein structures revealed the molecular basis responsible for its potency and selectivity.

  DOI：

  10.1021/jm061368v
• 作为产物：
  描述：

  2-羟基-5-(羟基甲基)苯甲醛 在 吡啶 、 氯化亚砜 作用下， 以 二氯甲烷 为溶剂， 反应 4.0h， 生成 chloride of 6-chloromethyl-2-oxo-2H-1-benzopyran-3-carboxylic acid
  参考文献：
  名称：

  新型活性探针用于人类细胞色素P450分析的合理开发。

  摘要：

  事实证明，生物样品中功能性细胞色素P450（CYP）的鉴定和定量对于药物功效和代谢处置的可靠分析非常重要。在这项研究中，合理设计和合成了一种新型的基于CYP活性的探针，证明了CYP亚型的选择性结合。探针结合对NADPH的存在的依赖性允许选择性检测功能活性CYP。这允许使用生化和蛋白质组学方法论和方法对这些酶进行检测和分析。

  DOI：

  10.1002/cmdc.201600134

文献信息

• Coumarinic derivatives as mechanism-based inhibitors of α-chymotrypsin and human leukocyte elastase
  作者：Lionel Pochet、Caroline Doucet、Georges Dive、Johan Wouters、Bernard Masereel、Michèle Reboud-Ravaux、Bernard Pirotte

  DOI：10.1016/s0968-0896(00)00071-7

  日期：2000.6

  inhibitory potency toward alpha-CT and HLE. Cycloalkyl esters and amides were found to be essentially inactive on both enzymes. On the opposite, aromatic esters strongly inactivated alpha-CT whereas HLE was less efficiently inhibited with dichlorophenyl ester derivatives (kinact/K(I) = 4000 M(-1) s(-1) for 36). Representative examples of amide, ester, thioester and ketone derivatives were prepared in order

  合成了新型香豆素衍生物，并测试了其对α-CT和HLE的抑制作用。发现环烷基酯和酰胺对两种酶基本上无活性。相反，芳香族酯强烈地使α-CT失活，而二氯苯基酯衍生物对HLE的抑制作用较弱（36的动力学/ K（I）= 4000 M（-1）s（-1））。制备酰胺，酯，硫代酯和酮衍生物的代表性实例，以评估香豆素环与苯基侧链之间的连接的影响。如修饰的胰凝乳蛋白酶的氨基酸分析所示，6-氯甲基衍生物不可逆地使α-CT失活是由于组氨酸残基的烷基化。相反，对HLE的抑制是短暂的。香豆素的内在反应性已使用配体与甲醇-水对之间的亲核反应模型进行了计算。从该计算看来，这些分子表达的抑制能力的差异不能仅通过内酯羰基对亲核攻击的反应性差异来解释。
• 6-Substituted 2-Oxo-2<i>H</i>-1-benzopyran-3-carboxylic Acid as a Core Structure for Specific Inhibitors of Human Leukocyte Elastase
  作者：Caroline Doucet、Lionel Pochet、Nicole Thierry、Bernard Pirotte、Jacques Delarge、Michèle Reboud-Ravaux

  DOI：10.1021/jm990070k

  日期：1999.10.1

  (k(i)/K(I) = 107 000 M(-1). s(-1) for 4c) and thrombin (k(i)/K(I) = 7 200 M(-1).s(-1) for 3b) as demonstrated by spontaneous or hydroxylamine-accelerated reactivation, irrespective of the nature of the substituent at the 6-position. Conversely, alpha-chymotrypsin was irreversibly inhibited by 6-chloromethyl derivatives (k(i)/K(I) = 107 400 M(-1). s(-1) for 3b). The presence of a latent alkylating function

  设计了6-取代的2-氧代-2H-1-苯并吡喃-3-羧酸的吡啶酯作为基于机制的人白细胞弹性蛋白酶抑制剂。系列4的化合物特异性抑制该酶。几种被测化合物（系列2和3）是人白细胞弹性蛋白酶和α-胰凝乳蛋白酶的有力的时间依赖性抑制剂。这些系列的某些化合物可抑制凝血酶。胰蛋白酶不受抑制。观察到人类白细胞弹性蛋白酶（k（i）/ K（I）= 107 000 M（-1）。s（-1）对于4c）和凝血酶（k（i）/ K（I）= 7）暂时失活200 m（-1）.s（-1）对于3b），通过自发或羟胺加速的再活化来证明，而与6位取代基的性质无关。相反，α-胰凝乳蛋白酶被6-氯甲基衍生物不可逆地抑制（k（i）/ K（I）= 107400 M（-1）。s（-1）for 3b）。导致这种失活需要在6-位（氯甲基）存在潜在的烷基化功能。在没有这种烷基化功能的情况下（系列4），人类白细胞弹性蛋白酶被特异性抑制，这表明该新系列的
• Esters and Amides of 6-(Chloromethyl)-2-oxo-2<i>H</i>-1-benzopyran-3-carboxylic Acid as Inhibitors of α-Chymotrypsin:  Significance of the “Aromatic” Nature of the Novel Ester-Type Coumarin for Strong Inhibitory Activity
  作者：Lionel Pochet、Caroline Doucet、Marc Schynts、Nicole Thierry、Nicole Boggetto、Bernard Pirotte、Kai Y. Jiang、Bernard Masereel、Pascal de Tullio、Jacques Delarge、Michèle Reboud-Ravaux

  DOI：10.1021/jm960090b

  日期：1996.1.1

  activity toward bovine alpha-chymotrypsin and human leukocyte elastase. Both series behaved as time-dependent inhibitors of alpha-chymotrypsin, but ester-type coumarins were clearly more efficient than the corresponding amides in inactivating the serine proteinase. The best inactivations were observed with "aromatic" esters, in particular with meta-substituted phenyl esters such as m-chlorophenyl 6-(chlor

  合成了一系列6-（氯甲基）-2-氧代-2H-1-苯并吡喃-3-羧酸的酯和酰胺，并在体外评估了它们对牛α-胰凝乳蛋白酶和人白细胞弹性蛋白酶的抑制活性。这两个系列均表现为α-胰凝乳蛋白酶的时间依赖性抑制剂，但酯型香豆素在灭活丝氨酸蛋白酶方面显然比相应的酰胺更有效。用“芳族”酯，尤其是间位取代的苯基酯，例如间氯苯基6-（氯甲基）-2-氧代-2H-1-苯并吡喃-3-羧酸酯，观察到最好的灭活。最强大的α-胰凝乳蛋白酶灭活剂（在pH 7.5和25摄氏度下，激酶/ KI = 760,000 M-1 S-1）的报道。通常，香豆素衍生物不能显着抑制人白细胞弹性蛋白酶。
• Coumarins as factor XIIa inhibitors: Potency and selectivity improvements using a fragment-based strategy
  作者：Clara Davoine、Amandine Traina、Jonathan Evrard、Steve Lanners、Marianne Fillet、Lionel Pochet

  DOI：10.1016/j.ejmech.2023.115636

  日期：2023.11

  a major part of the association energy. From the screening, we selected fragments displaying a micromolar activity and studied their selectivity on other serine proteases. Then, these fragments were merged to our coumarin templates, leading to the generation of nanomolar inhibitors. The mechanism of inhibition was further studied by mass spectrometry demonstrating the covalent binding through the formation

  之前，我们描述了 XIIa 因子的弱香豆素抑制剂，这是人工表面诱导的血栓形成和各种炎症性疾病的有希望的靶标。在这项工作中，我们使用基于片段的药物发现方法来改进我们的香豆素系列。首先，我们筛选了 S1 口袋的约 200 个片段。胰蛋白酶样丝氨酸蛋白酶（例如因子 XIIa）的 S1 口袋高度保守，并且已知驱动大部分缔合能量。通过筛选，我们选择了具有微摩尔活性的片段，并研究了它们对其他丝氨酸蛋白酶的选择性。然后，这些片段被合并到我们的香豆素模板中，从而产生纳摩尔抑制剂。通过质谱法进一步研究了抑制机制，证明了通过形成酰基酶复合物的共价结合。在血浆中测试了最有效的化合物，以评估其在凝血试验中的稳定性和功效。它的血浆半衰期为 1.9 小时，并且对内源性凝血途径比外源性凝血途径具有良好的选择性。
• Investigation of mechanism-based thrombin inhibitors: Implications of a highly conserved water molecule for the binding of coumarins within the S pocket
  作者：Raphaël Frédérick、Caroline Charlier、Séverine Robert、Johan Wouters、Bernard Masereel、Lionel Pochet

  DOI：10.1016/j.bmcl.2005.12.070

  日期：2006.4

  The synthesis of novel coumarins bearing on the lateral side chain in the 3-position an amine or a guanidine group is described. In vitro evaluation highlighted 14d which possesses a meta aniline side chain as a very potent THR inhibitor. Surprisingly, the introduction of a guanidine moiety always led to a decrease in THR inhibiting properties. We, thus, used docking experiments to rationalize the SAR in the series. This study showed the crucial role of a conserved water molecule in the specificity pocket of THR during docking simulation in order to explain the inactivity of guanidine derivatives. (C) 2006 Elsevier Ltd. All rights reserved.