1-(3-(tert-butyl)-1-(2-hydroxy-2-phenylethyl)-1H-pyrazol-5-yl)-3-(4-fluorophenyl)urea

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 1-(3-(tert-butyl)-1-(2-hydroxy-2-phenylethyl)-1H-pyrazol-5-yl)-3-(4-fluorophenyl)urea
• 英文别名: 1-[5-Tert-butyl-2-(2-hydroxy-2-phenylethyl)pyrazol-3-yl]-3-(4-fluorophenyl)urea；1-[5-tert-butyl-2-(2-hydroxy-2-phenylethyl)pyrazol-3-yl]-3-(4-fluorophenyl)urea
• 化学式: C₂₂H₂₅FN₄O₂
• 分子量: 396.465
• InChiKey: BJKHCWYOZIDBLE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  29
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  79.2
• 氢给体数：
  3
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  2-hydrazino-1-phenylethanol 在 溶剂黄146 作用下， 以 乙醇 、 甲苯 为溶剂， 反应 22.0h， 生成 1-(3-(tert-butyl)-1-(2-hydroxy-2-phenylethyl)-1H-pyrazol-5-yl)-3-(4-fluorophenyl)urea
  参考文献：
  名称：

  Design, synthesis and biological evaluation of new pyrazolyl-ureas and imidazopyrazolecarboxamides able to interfere with MAPK and PI3K upstream signaling involved in the angiogenesis

  摘要：

  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.

  DOI：

  10.1016/j.ejmech.2017.03.066

文献信息

• Microbiological Screening of 5-Functionalized Pyrazoles for the Future Development of Optimized Pyrazole-Based Delivery Systems
  作者：Chiara Brullo、Debora Caviglia、Andrea Spallarossa、Silvana Alfei、Scott G. Franzblau、Bruno Tasso、Anna Maria Schito

  DOI：10.3390/pharmaceutics14091770

  日期：——

  The pyrazole ring represents a widely applied chemical scaffold in medicinal chemistry research and we have observed that the physicochemical and biological features of highly substituted pyrazoles can be successfully improved by their encapsulation in dendrimer nanoparticles (NPs). For the future development of new optimized antibacterial delivery systems, we report the synthesis and biological evaluation of 5-amino functionalized pyrazole library (compounds 2–7). In detail, new derivatives 2–7 were differently decorated in C3, C4 and C5 positions. An in silico study predicted pyrazoles 2–7 to exert good drug-like and pharmacokinetic properties. Compounds 3c and 4b were endowed with moderate, but nanotechnologically improvable activity against multidrug-resistant (MDR) clinical isolates of Gram-positive species, especially of the Staphylococcus genus (MICs = 32–64 µg/mL). In addition, derivatives 3c and 4a showed moderate activities against Mycobacterium tuberculosis and 4a evidenced activity also against MDR strains. Overall, the collected evidence supported that, upon nano-formulation with proper polymer matrices, the new synthesized compounds could provide new pyrazole-based drug delivery systems with an enhanced and enlarged-spectrum of antibacterial activity.

  吡唑环是药物化学研究中广泛应用的化学支架，我们观察到高度取代的吡唑可以通过封装在树枝状聚合物纳米颗粒（NPs）中成功地改善其物理化学和生物学特性。为了将来开发新的优化抗菌给药系统，我们报告了 5-氨基功能化吡唑库（化合物 2-7）的合成和生物学评价。具体而言，新衍生物 2-7 在 C3、C4 和 C5 位置上进行了不同的装饰。硅学研究预测吡唑 2-7 具有良好的类药物和药代动力学特性。化合物 3c 和 4b 对革兰氏阳性菌（尤其是葡萄球菌属）的耐多药（MDR）临床分离株具有中度活性，但通过纳米技术可提高活性（MICs = 32-64 µg/mL）。此外，衍生物 3c 和 4a 对结核分枝杆菌表现出中等活性，4a 对 MDR 菌株也有活性。总之，收集到的证据表明，在与适当的聚合物基质进行纳米配制后，新合成的化合物可提供新的吡唑类给药系统，并能增强和扩大抗菌谱。
• 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.