1-(3,4-二氯苯基)-4-甲基-5-(1H-吡咯-1-基)-1H-吡唑-3-羧酸 | 1015765-72-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 中文名称: 1-(3,4-二氯苯基)-4-甲基-5-(1H-吡咯-1-基)-1H-吡唑-3-羧酸
• 英文名称: 1-(3,4-dichlorophenyl)-4-methyl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxylic acid
• 英文别名: 1-(3,4-Dichlorophenyl)-4-methyl-5-pyrrol-1-ylpyrazole-3-carboxylic acid
• CAS: 1015765-72-6
• 化学式: C₁₅H₁₁Cl₂N₃O₂
• 分子量: 336.177
• InChiKey: GLWWPTMCIUEDQR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  22
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.07
• 拓扑面积：
  60
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  1-(3,4-二氯苯基)-4-甲基-5-(1H-吡咯-1-基)-1H-吡唑-3-羧酸 、 金刚烷胺 在 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 二氯甲烷 为溶剂， 以97%的产率得到N-(adamant-1-yl) 1-(3,4-dichlorophenyl)-4-methyl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamide
  参考文献：
  名称：

  新取代的1-芳基-5-（1 H-吡咯-1-基）-1 H-吡唑-3-羧酰胺的合成，大麻素受体亲和力，分子模型研究和体内药理学评估。2. 3-羧酰胺取代基对亲和力和选择性的影响

  摘要：

  通过取代先前报道的3-羧酰胺氮上的2,4-二氯苄基和环己基部分，合成了新的取代的1-芳基-5-（1 H-吡咯-1-基）-1 H-吡唑-3-羧酰胺CB 1受体拮抗剂/反向激动剂4和5。几个配体显示了强的亲合性为HCB 1受体，具有ķ我浓度下媲美的参考化合物1，4和5，并显示出CB 1选择性比得上1和2。对接实验和分子动力学（MD）模拟解释了化合物31和37与hCB 1的强结合亲和力。根据我们以前的研究，31和37与K3.28（192）形成H键，这说明对受体无活性状态和反向激动剂活性具有高亲和力。在对大鼠急性给药后发现食物摄入受到抑制，这支持了CB 1选择性化合物4和52充当拮抗剂/反向激动剂的概念。

  DOI：

  10.1016/j.bmc.2009.06.027
• 作为产物：
  描述：

  ethyl 1-(3,4-dichlorophenyl)-4-methyl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxylate 在 lithium hydroxide 作用下， 以 四氢呋喃 、 水 为溶剂， 以99%的产率得到1-(3,4-二氯苯基)-4-甲基-5-(1H-吡咯-1-基)-1H-吡唑-3-羧酸
  参考文献：
  名称：

  Synthesis, Cannabinoid Receptor Affinity, and Molecular Modeling Studies of Substituted 1-Aryl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamides

  摘要：

  The new 1-phenyl-5-(1H-pyrrol-1-yl)pyrazole-3-carboxamides were compared with the reference compounds AM251 and SR144528 for cannabinoid hCB(1) and hCB(2) receptor affinity. Compounds bearing 2,4-dichlorophenyl or 2,4-difluorophenyl groups at position 1 and 2,5-dimethylpyrrole moiety at position 5 of the pyrazole nucleus were generally more selective for hCB(1). On the other hand, the N-cyclohexyl group at the 3-carboxamide was the determinant for the hCB2 selectivity, in particular when a 3,4-dichlorophenyl group was also present at position 1. Compound 26 was the most selective ligand for the hCB(1) receptor (K-i (CB2)/K-i (CB1) = 140.7). Derivative 30, the most potent hCB(1) ligand (Ki = 5.6 nM), was equipotent to AM251 and behaved as an inverse agonist in the cAMP assay (EC50 similar to 1 nM). The carbonyl oxygen of both 26 and 30 formed a H-bond with K3.28(192), while the substituents at the nitrogen fitted in a pocket formed by lipophilic residues. This H-bonding interaction was proposed to account for the high affinity for receptors' inactive state and the inverse agonist activity.

  DOI：

  10.1021/jm070566z

文献信息

• Optimization of Pyrazole Compounds as Antibiotic Adjuvants Active against Colistin- and Carbapenem-Resistant Acinetobacter baumannii
  作者：Filomena Sannio、Antonella Brizzi、Rosita Del Prete、Marialuce Avigliano、Tiziana Simone、Carlotta Pagli、Teresa Ferraro、Filomena De Luca、Marco Paolino、Federico Corelli、Claudia Mugnaini、Jean-Denis Docquier

  DOI：10.3390/antibiotics11121832

  日期：——

  Furthermore, an evaluation of their activity as potential antibiotic adjuvants allowed for the identification of two highly active compounds on MDR Acinetobacter baumannii, including colistin-resistant isolates. This work confirms the interest in pyrazole amides as a starting point for the optimization of synergistic antibacterial compounds active on antibiotic-resistant, Gram-negative pathogens.

  抗生素耐药性、革兰氏阴性、机会性病原体的扩散是一个日益重要的全球公共卫生问题，造成了巨大的社会经济负担。鲍曼不动杆菌分离株尽管引起的感染数量少于肠杆菌，但通常表现出多重耐药表型。碳青霉烯类耐药性也相当普遍，促使 WHO 将耐碳青霉烯类鲍曼不动杆菌列为发现和开发新抗菌剂的“关键优先事项”。在之前的工作中，我们确定了几个系列的化合物，这些化合物对相关的革兰氏阴性菌（包括鲍曼不动杆菌）显示出直接作用或协同作用。其中，两种吡唑化合物，尽管没有任何直接作用活性，在存在亚抑制浓度的粘菌素对肺炎克雷伯菌和鲍曼不动杆菌时显示出显着的协同活性，并作为合成新类似物的起点。在这项工作中，合成了一系列新的 47 种吡唑化合物。一些化合物对革兰氏阳性菌表现出显着的直接抗菌活性。此外，通过评估它们作为潜在抗生素佐剂的活性，可以鉴定出两种对 MDR 鲍曼不动杆菌具有高度活性的化合物，包括粘菌素耐药株。这项工作证实了人们
• Synthesis, Cannabinoid Receptor Affinity, and Molecular Modeling Studies of Substituted 1-Aryl-5-(1<i>H</i>-pyrrol-1-yl)-1<i>H</i>-pyrazole-3-carboxamides
  作者：Romano Silvestri、Maria Grazia Cascio、Giuseppe La Regina、Francesco Piscitelli、Antonio Lavecchia、Antonella Brizzi、Serena Pasquini、Maurizio Botta、Ettore Novellino、Vincenzo Di Marzo、Federico Corelli

  DOI：10.1021/jm070566z

  日期：2008.3.1

  The new 1-phenyl-5-(1H-pyrrol-1-yl)pyrazole-3-carboxamides were compared with the reference compounds AM251 and SR144528 for cannabinoid hCB(1) and hCB(2) receptor affinity. Compounds bearing 2,4-dichlorophenyl or 2,4-difluorophenyl groups at position 1 and 2,5-dimethylpyrrole moiety at position 5 of the pyrazole nucleus were generally more selective for hCB(1). On the other hand, the N-cyclohexyl group at the 3-carboxamide was the determinant for the hCB2 selectivity, in particular when a 3,4-dichlorophenyl group was also present at position 1. Compound 26 was the most selective ligand for the hCB(1) receptor (K-i (CB2)/K-i (CB1) = 140.7). Derivative 30, the most potent hCB(1) ligand (Ki = 5.6 nM), was equipotent to AM251 and behaved as an inverse agonist in the cAMP assay (EC50 similar to 1 nM). The carbonyl oxygen of both 26 and 30 formed a H-bond with K3.28(192), while the substituents at the nitrogen fitted in a pocket formed by lipophilic residues. This H-bonding interaction was proposed to account for the high affinity for receptors' inactive state and the inverse agonist activity.
• Synthesis, cannabinoid receptor affinity, molecular modeling studies and in vivo pharmacological evaluation of new substituted 1-aryl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamides. 2. Effect of the 3-carboxamide substituent on the affinity and selectivity profile
  作者：Romano Silvestri、Alessia Ligresti、Giuseppe La Regina、Francesco Piscitelli、Valerio Gatti、Antonella Brizzi、Serena Pasquini、Antonio Lavecchia、Marco Allarà、Noemi Fantini、Mauro Antonio Maria Carai、Ettore Novellino、Giancarlo Colombo、Vincenzo Di Marzo、Federico Corelli

  DOI：10.1016/j.bmc.2009.06.027

  日期：2009.8

  New substituted 1-aryl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamides were synthesized by replacing the 2,4-dichlorobenzyl and cyclohexyl moieties at the 3-carboxamide nitrogen of the previously reported CB1 receptor antagonists/inverse agonists 4 and 5. Several ligands showed potent affinity for the hCB1 receptor, with Ki concentrations comparable to the reference compounds 1, 4 and 5, and exhibited

  通过取代先前报道的3-羧酰胺氮上的2,4-二氯苄基和环己基部分，合成了新的取代的1-芳基-5-（1 H-吡咯-1-基）-1 H-吡唑-3-羧酰胺CB 1受体拮抗剂/反向激动剂4和5。几个配体显示了强的亲合性为HCB 1受体，具有ķ我浓度下媲美的参考化合物1，4和5，并显示出CB 1选择性比得上1和2。对接实验和分子动力学（MD）模拟解释了化合物31和37与hCB 1的强结合亲和力。根据我们以前的研究，31和37与K3.28（192）形成H键，这说明对受体无活性状态和反向激动剂活性具有高亲和力。在对大鼠急性给药后发现食物摄入受到抑制，这支持了CB 1选择性化合物4和52充当拮抗剂/反向激动剂的概念。