1-(7-chloroquinolin-4-yl)-5-(4-fluorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid | 1490390-43-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 1-(7-chloroquinolin-4-yl)-5-(4-fluorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid
• CAS: 1490390-43-6
• 化学式: C₂₀H₁₃ClFN₃O₂
• 分子量: 381.794
• InChiKey: UPWMNQFBVFUBQE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.89
• 重原子数：
  27.0
• 可旋转键数：
  3.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.05
• 拓扑面积：
  68.01
• 氢给体数：
  1.0
• 氢受体数：
  4.0

反应信息

• 作为反应物：
  描述：

  1-(7-chloroquinolin-4-yl)-5-(4-fluorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid 在 氯化亚砜 、 N,N-二异丙基乙胺 作用下， 以 氯仿 、 甲苯 为溶剂， 反应 6.5h， 生成 1-(7-chloroquinolin-4-yl)-5-(4-fluorophenyl)-4-methyl-N-(1-piperidinyl)-1H-pyrazole-3-carboxamide
  参考文献：
  名称：

  Synthesis, hypoglycemic activity and molecular modeling studies of pyrazole-3-carbohydrazides designed by a CoMFA model

  摘要：

  Diabetes and obesity are two universal health problems that constitute a research objective of several groups due to the lack of efficient and safe drug treatment. In this sense, cannabinoid receptor 1 (CBI) has attracted interest because of its role in food intake and metabolic balance, two targets in the control of metabolic syndrome. In this work, novel 1,5-diaryl pyrazole derivatives were synthesized in accordance with the pKi prediction of a previously reported CoMFA model by our group. To further investigate the biological activity of these compounds in metabolic disorders, their hypoglycemic activity in an in vivo model was tested. Interestingly, a high degree of correlation was observed between the predicted pK(i) and hypoglycemic effect 7 h after administration. Compounds 4, 9 and 13 showed the most significant plasma glucose reduction with decreases of 60%, 64% and 60% respectively. This result not only surpasses the activity of the lead rimonabant, but also that of the reference drug glibenclamide. Moreover, PASS prediction and molecular docking in an excellent validated homology model of CBI suggest that these compounds would probably act as CBI antagonists/inverse agonists and therefore, antiobesity agents. The ligand receptor complexes demonstrate that 1,5-diaryl pyrazole derivatives bind to the proposed binding site where a hydrophobic moiety interacts with the phenyl rings in the pyrazole nucleus and Lys192 forms a hydrogen bond with the oxygen of the carbonyl group. Dynamics simulations were also carried out to study the stability of the ligand receptor complexes where the most active compounds showed smaller Delta G values and more hydrogen bonds throughout the simulation. These compounds are considered useful leads for further optimization in the treatment of such metabolic illnesses. (C) 2013 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2013.07.054
• 作为产物：
  描述：

  ethyl 4-(4-fluorophenyl)-3-methyl-2,4-dioxobutanoate lithium salt 在 硫酸 、 potassium hydroxide 作用下， 以 乙醇 为溶剂， 反应 20.0h， 生成 1-(7-chloroquinolin-4-yl)-5-(4-fluorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid
  参考文献：
  名称：

  1,5-Diarylpyrazole and vanillin hybrids: Synthesis, biological activity and DFT studies

  摘要：

  Herein, we report the design and synthesis of 13 diarylpyrazole hybrids with vanillin constructed as dual compounds against oxidative stress and diabetes. Compounds were tested in two different antioxidant assays. It was found that all compounds showed an important antioxidant activity in both DPPH and ORAC models and the activity was even more remarkable than vanillin. In addition, the hypoglycemic effect of compounds 1, 2, 4 and 12 was evaluated. Interestingly, compound 1 had the most potent hypoglycemic effect with a glycemia reduction of 71%, which was higher than rimonabant. Finally, a DFT study to propose a reasonable antioxidant mechanism is detailed. Both thermodynamic and kinetic studies indicated that the most feasible mechanism consists in the HAT abstraction of the phenolic hydrogen due to the formation of an stable transition state through the most rapid and exergonic path, while the SPLET mechanism is the most significant at higher pH values. (C) 2015 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2015.06.010