ethyl 2-phenyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazole-7-carboxylate | 946150-83-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: ethyl 2-phenyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazole-7-carboxylate
• 英文别名: 2-phenyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazole-7-carboxylic acid ethyl ester
• CAS: 946150-83-0
• 化学式: C₁₄H₁₅N₃O₂
• 分子量: 257.292
• InChiKey: PDCZUYSAODBVDC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  19
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  56.2
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  ethyl 2-phenyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazole-7-carboxylate 在 sodium hydroxide 作用下， 反应 4.0h， 以79%的产率得到2-phenyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazole-7-carboxylic acid
  参考文献：
  名称：

  2-Phenyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazole derivatives: New potent inhibitors of fMLP-induced neutrophil chemotaxis

  摘要：

  It is well known that both acute and chronic autoimmune inflammatory disorders arise following a breakdown in control of neutrophil activation and recruitment. In the search for new anti-inflammatory agents, we synthesized some new 2-phenyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazole derivatives and tested them in vitro in order to evaluate their ability to interfere with human neutrophil functions. All tested compounds showed strong inhibition of fMLP-OMe-induced chemotaxis, although they appeared unable to block degranulation and the fMLP-OMe-induced respiratory burst, and were inactive in binding experiments. (c) 2007 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2007.04.036
• 作为产物：
  描述：

  2-hydrazino-1-phenylethanol 在 硫酸 作用下， 以 甲苯 为溶剂， 反应 8.17h， 生成 ethyl 2-phenyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazole-7-carboxylate
  参考文献：
  名称：

  Insights into the Pharmacological Activity of the Imidazo−Pyrazole Scaffold

  摘要：

  摘要 在之前的研究中，我们合成了不同的咪唑吡唑 1 和 2，它们具有有趣的抗癌、抗血管生成和抗炎活性。为了进一步扩展咪唑吡唑支架的结构-活性关系，并鉴定具有多靶点机制的潜在活性的新型抗增殖/抗炎剂，我们设计并合成了化合物库 3-5。这些新型衍生物的化学修饰特征包括：i）用具有不同电子、立体和亲油特性的基团装饰儿茶酚环（化合物 3）；ii）在咪唑吡唑支架的 C-6 上插入一个甲基（化合物 4）；iii）将酰肼取代基从咪唑吡唑子结构的第 7 位移到第 6 位（化合物 5）。对所有合成的化合物都进行了癌症和正常细胞系的测试。衍生物 3 a、3 e、4 c、5 g 和 5 h 对所选肿瘤细胞系的 IC50 值均在较低的微摩尔范围内，并证明具有抗氧化特性，能够抑制人体血小板中 ROS 的产生。硅学计算预测，最有前途的化合物具有良好的类药物和药代动力学特性。此外，分子对接和分子动力学模拟表明，最有活性的衍生物 3 e 能够与聚合管蛋白 α/tubulin β/stathmin4 复合物中的秋水仙碱结合位点相互作用。

  DOI：

  10.1002/cmdc.202300252

文献信息

• New Hybrid Pyrazole and Imidazopyrazole Antinflammatory Agents Able to Reduce ROS Production in Different Biological Targets
  作者：Chiara Brullo、Matteo Massa、Federica Rapetti、Silvana Alfei、Maria B. Bertolotto、Fabrizio Montecucco、Maria Grazia Signorello、Olga Bruno

  DOI：10.3390/molecules25040899

  日期：——

  scaffolds (pyrazole and imidazopyrazole) and the substituted catechol moiety were determinant for the pharmacodynamic properties, even if hybrid molecules bearing to the pyrazole series were more active than the imidazopyrazole ones. In addition, the pivotal role of the catechol substituents has been analyzed. In conclusion the hybridization approach gave a new serie of multitarget antiinflammatory compounds

  我们最近报道了几种基于吡唑和咪唑吡唑支架的抗炎剂以及大量取代儿茶酚 PDE4D 抑制剂。为了获得可能作用于参与炎症发作的不同靶点的新分子，我们通过酰腙链将吡唑和咪唑并吡唑支架与不同修饰的儿茶酚部分连接，设计并合成了一系列杂化化合物。一些化合物表现出抗氧化活性，可抑制中性粒细胞中活性氧 (ROS) 的升高，并对 4D 型磷酸二酯酶，特别是 4B 型磷酸二酯酶（与炎症最相关的亚型）具有良好的抑制作用。此外，大多数化合物还抑制血小板中ROS的产生，证实了它们通过两种独立机制发挥抗炎反应的能力。构效关系（SAR）分析证明，杂环支架（吡唑和咪唑并吡唑）和取代的儿茶酚部分对药效特性具有决定性作用，即使吡唑系列的杂化分子比咪唑并吡唑的活性更高。此外，还分析了儿茶酚取代基的关键作用。总之，杂交方法产生了一系列新的多靶点抗炎化合物，其特点是在不同的生物靶点上具有很强的抗氧化活性。
• Discovery of New Antiproliferative Imidazopyrazole Acylhydrazones Able To Interact with Microtubule Systems
  作者：Chiara Brullo、Federica Rapetti、Silvana Alfei、Irena Maric、Francesca Rizzelli、Marina Mapelli、Camillo Rosano、Maurizio Viale、Olga Bruno

  DOI：10.1002/cmdc.202000122

  日期：2020.6.4

  Even though immunotherapy has radically changed the search for anticancer therapies, there are still many different pathways that are open to intervention with traditional small molecules. To expand our investigation in the anticancer field, we report here a new series of compounds in which our previous pyrazole and imidazopyrazole scaffolds are linked to a differently decorated phenyl ring through

  即使免疫疗法从根本上改变了对抗癌疗法的寻求，但仍有许多不同的途径可供传统小分子干预。为了扩大我们在抗癌领域的研究，我们在此报告了一系列新化合物，其中我们以前的吡唑和咪唑并吡唑支架通过酰基hydr连接基连接到装饰不同的苯环上。在库中的初步测试是在美国国家癌症研究所针对完整的NCI 60细胞面板进行的。然后通过免疫荧光染色测试了咪唑并吡唑系列中最好的化合物对细胞增殖，凋亡诱导的抑制作用及其对细胞周期和微管的影响。两种化合物低微摩尔范围内有50个值，并诱导凋亡。两种化合物都随着多倍体细胞的出现改变了细胞周期阶段。免疫荧光分析表明微管发生改变；微管蛋白聚合分析和对接研究表明，微管蛋白系统可能是此处报道的新酰基hydr系列的靶标，尽管并非唯一。
• 2-Phenyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazole derivatives: New potent inhibitors of fMLP-induced neutrophil chemotaxis
  作者：Olga Bruno、Chiara Brullo、Francesco Bondavalli、Angelo Ranise、Silvia Schenone、Maria Sofia Falzarano、Katia Varani、Susanna Spisani

  DOI：10.1016/j.bmcl.2007.04.036

  日期：2007.7

  It is well known that both acute and chronic autoimmune inflammatory disorders arise following a breakdown in control of neutrophil activation and recruitment. In the search for new anti-inflammatory agents, we synthesized some new 2-phenyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazole derivatives and tested them in vitro in order to evaluate their ability to interfere with human neutrophil functions. All tested compounds showed strong inhibition of fMLP-OMe-induced chemotaxis, although they appeared unable to block degranulation and the fMLP-OMe-induced respiratory burst, and were inactive in binding experiments. (c) 2007 Elsevier Ltd. All rights reserved.
• N-Aryl-2-phenyl-2,3-dihydro-imidazo[1,2-b]pyrazole-1-carboxamides 7-substituted strongly inhibiting both fMLP-OMe- and IL-8-induced human neutrophil chemotaxis
  作者：Chiara Brullo、Susanna Spisani、Rita Selvatici、Olga Bruno

  DOI：10.1016/j.ejmech.2011.11.031

  日期：2012.1

  Anomalous activation of neutrophil recruitment is one of the causes of many inflammatory diseases. The chemoattractants N-formyl-methionyl-leucyl-phenylalanine (fMLP), and interleukine 8 (IL8) play a pivotal role in neutrophil chemotaxis regulation in the latter and early stages, respectively, probably by two independent mechanisms. We reported here synthesis and biological evaluation of new N-aryl-2-pheny1-2,3-dihydro-imidazo[1,2-b]pyrazole-1-carboxamides 7-substituted which were designed as possible multi-target antiinflammatory agents. Many of the title compounds showed a good inhibition, in the nano molar range, of human neutrophil chemotaxis selectively acting toward fMLP-OMe (methylester of fMLP) or IL8 stimulus; whereas, two compounds showed an interesting dual activity inhibiting both fMLP-OMe and IL8-induced chemotaxis at nano molar concentration. (C) 2011 Elsevier Masson SAS. All rights reserved.
• Design, synthesis and biological evaluation of new pyrazolyl-ureas and imidazopyrazolecarboxamides able to interfere with MAPK and PI3K upstream signaling involved in the angiogenesis
  作者：Elda Meta、Chiara Brullo、Adama Sidibe、Beat A. Imhof、Olga Bruno

  DOI：10.1016/j.ejmech.2017.03.066

  日期：2017.6

  Taking into account the structure activity relationship information given by our previous studies, we designed and synthesized a small library of pyrazolylureas and imidazopyrazolecarboxamides fluorinated on urea moiety and differently decorated on pyrazole nucleus. All compounds were preliminary screened by Western blotting technique to evaluate their activity on MAPK and PI3K pathways by monitoring ERK1/2, p38MAPK and Akt phosphorylation, and also screened with a wound healing assay to assess their capacity in inhibiting endothelial cell migration, using human umbilical vein endothelial cells stimulated with VEGF. Pyrazoles and imidazopyrazoles did not show the same activity profile. SAR consideration showed that specific substituents and their position in pyrazole nucleus, as well as the type of substituent on the phenylurea moiety play a pivotal role in determining increase or decrease of kinases phosphorylation. On the other hand the loss of flexibility in imidazopyrazole derivatives is responsible for activity potentiation. Screening of the compound library for inhibition of endothelial cell migration, a function required for angiogenesis, showed significant activity for compound 3. This compound might interfere with cell migration by modulating the activity of different upstream target kinases. Therefore, compound 3 represents a potential inhibitor of angiogenesis. Furthermore, it may be used as a tool to identify unknown mediators of endothelial migration and thereby unveiling new therapeutic targets for controlling pathological angiogenesis in diseases such as cancers. (C) 2017 Elsevier Masson SAS. All rights reserved.