1-(4-氯苯基)-4-甲基-5-(1H-吡咯-1-基)-1H-吡唑-3-羧酸 | 1015765-68-0

• 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-(4-氯苯基)-4-甲基-5-(1H-吡咯-1-基)-1H-吡唑-3-羧酸
• 英文名称: 1-(4-chlorophenyl)-4-methyl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxylic acid
• 英文别名: 1-(4-Chlorophenyl)-4-methyl-5-pyrrol-1-ylpyrazole-3-carboxylic acid
• CAS: 1015765-68-0
• 化学式: C₁₅H₁₂ClN₃O₂
• 分子量: 301.732
• InChiKey: UGKDQSUCTMXSNH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  21
• 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-(4-氯苯基)-4-甲基-5-(1H-吡咯-1-基)-1H-吡唑-3-羧酸 以 四氢呋喃 为溶剂， 反应 26.0h， 生成 N,1-bis(4-chlorophenyl)-4-methyl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamide
  参考文献：
  名称：

  New 1-phenyl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamides inhibit hepatitis C virus replication via suppression of cyclooxygenase-2

  摘要：

  We report here the synthesis and mechanism of inhibition of pyrazolecarboxamide derivatives as a new class of HCV inhibitors. Compounds 6, 7, 8 and 16 inhibited the subgenomic HCV replicon lb genotype at EC50 values between 5 and 8 mu M and displayed an even higher potency against the infectious Jc1 HCV 2a genotype. Compound 6 exhibited an EC50 of 6.7 mu M and selectivity index of 23 against HCV 1b, and reduced the RNA copies of the infectious Jc1 chimeric 2a clone by 82% at 7 mu M. Evaluation of the mode of anti-HCV activity of 6 revealed that it suppressed HCV-induced COX-2 mRNA and protein expression, displaying an IC50 of 3.2 mu M in COX-2 promoter-linked luciferase reporter assay. Conversely, the anti-HCV activity of 6 was abrogated upon over-expression of COX-2. These findings suggest that 6 as a representative of these pyrazolecarboxamides function as anti-HCV agents via targeting COX-2 at both the transcription and translation levels. (C) 2014 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2014.11.042
• 作为产物：
  描述：

  ethyl 1-(4-chlorophenyl)-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96%的产率得到1-(4-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
• Rimonabant-Based Compounds Bearing Hydrophobic Amino Acid Derivatives as Cannabinoid Receptor Subtype 1 Ligands
  作者：Szabolcs Dvorácskó、Marilisa Pia Dimmito、Jessica Sebastiani、Giuseppe La Regina、Romano Silvestri、Stefano Pieretti、Azzurra Stefanucci、Csaba Tömböly、Adriano Mollica

  DOI：10.1021/acsmedchemlett.3c00024

  日期：——

  acids related to the cannabinoid type 1 (CB1) receptor antagonist rimonabant were amidated with valine or tert-leucine, and the resulting acids were further diversified as methyl esters, amides, and N-methyl amides. In vitro receptor binding and functional assays demonstrated a wide series of activities related to the CB1 receptors (CB1Rs). Compound 34 showed a high CB1R binding affinity (Ki = 6.9

  在这项研究中，与大麻素 1 型 (CB1) 受体拮抗剂利莫那班相关的1 H-吡唑-3-羧酸用缬氨酸或叔亮氨酸酰胺化，生成的酸进一步多样化为甲酯、酰胺和N-甲基酰胺。体外受体结合和功能测定证明了与 CB1 受体 (CB1Rs) 相关的一系列广泛活动。化合物34显示出高 CB1R 结合亲和力 ( K i = 6.9 nM) 和激动剂活性 (EC 50 = 46 nM；E max = 135%)。放射性配体结合和 [ 35S]GTPγS 结合测定也证明了其对 CB1Rs 的选择性和特异性。此外，体内实验表明，在福尔马林试验的早期，34比CB1激动剂WIN55,212-2的作用略强，镇痛作用持续时间较短。有趣的是，在酵母聚糖诱导的后肢水肿小鼠模型中，34能够在皮下注射后 24 小时内将足爪体积百分比保持在 75% 以下。腹膜内给药后，34增加了小鼠的食物摄入量，表明对 CB1Rs 具有潜在活性。
• Screen of Unfocused Libraries Identified Compounds with Direct or Synergistic Antibacterial Activity
  作者：Claudia Mugnaini、Filomena Sannio、Antonella Brizzi、Rosita Del Prete、Tiziana Simone、Teresa Ferraro、Filomena De Luca、Federico Corelli、Jean-Denis Docquier

  DOI：10.1021/acsmedchemlett.9b00674

  日期：2020.5.14

  Antibiotic resistance is an increasingly important global public health issue, as major opportunistic pathogens are evolving toward multidrug- and pan-drug resistance phenotypes. New antibiotics are thus needed to maintain our ability to treat bacterial infections. According to the WHO, carbapenem-resistant Acinetobacter, Enterobactericaeae, and Pseudomonas are the most critical targets for the development of new antibacterial drugs. An automated phenotypic screen was implemented to screen 634 synthetic compounds obtained in-house for both their direct-acting and synergistic activity. Fourteen percent and 10% of the compounds showed growth inhibition against tested Gram-positive and Gram-negative bacteria, respectively. The most active direct-acting compounds showed a broad-spectrum antibacterial activity, including on some multidrug-resistant clinical isolates. In addition, 47 compounds were identified for their ability to potentiate the activity of other antibiotics. Compounds of three different scaffolds (2-quinolones, phenols, and pyrazoles) showed a strong potentiation of colistin, some being able to revert colistin resistance in Acinetobacter baumannii.