1-(4-(cyclopentylethynyl)phenyl)-4-(1-(2-(4,5-dihydro-1H-imidazol-2-yl)hydrazono)ethyl)-5-methyl-1H-pyrazole

• 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-(4-(cyclopentylethynyl)phenyl)-4-(1-(2-(4,5-dihydro-1H-imidazol-2-yl)hydrazono)ethyl)-5-methyl-1H-pyrazole
• 化学式: C₂₂H₂₆N₆
• 分子量: 374.489
• InChiKey: IMHLRHHVNNQQLQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.0
• 重原子数：
  28.0
• 可旋转键数：
  3.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  66.6
• 氢给体数：
  2.0
• 氢受体数：
  6.0

反应信息

• 作为产物：
  描述：

  3-dimethylaminomethylenepentane-2,4-dione 在 盐酸 、 bis-triphenylphosphine-palladium(II) chloride 、 copper(l) iodide 、 三乙胺 作用下， 以 乙二醇二甲醚 、 乙醇 、 水 为溶剂， 反应 44.0h， 生成 1-(4-(cyclopentylethynyl)phenyl)-4-(1-(2-(4,5-dihydro-1H-imidazol-2-yl)hydrazono)ethyl)-5-methyl-1H-pyrazole
  参考文献：
  名称：

  From Phenylthiazoles to Phenylpyrazoles: Broadening the Antibacterial Spectrum toward Carbapenem-Resistant Bacteria

  摘要：

  The narrow antibacterial spectrum of phenylthiazole antibiotics was expanded by replacing central thiazole with a pyrazole ring while maintaining its other pharmacophoric features. The most promising derivative, compound 23, was more potent than vancomycin against multidrug-resistant Gram-positive clinical isolates, including vancomycin- and linezolid-resistant methicillin-resistant Staphylococcus aureus (MRSA), with a minimum inhibitory concentration (MIC) value as low as 0.5 mu g/mL. Moreover, compound 23 was superior to imipenem and meropenem against highly pathogenic carbapenem-resistant strains, such as Acinetobacter baumannii, Klebsiella pneumoniae, and Escherichia coli. In addition to the notable biofilm inhibition activity, compound 23 outperformed both vancomycin and kanamycin in reducing the intracellular burden of both Gram-positive and Gram-negative pathogenic bacteria. Compound 23 cleared 90% of intracellular MRSA and 98% of Salmonella enteritidis at 2X the MIC. Moreover, preliminary pharmacokinetic investigations indicated that this class of novel antibacterial compounds is highly metabolically stable with a biological half-life of 10.5 h, suggesting a once-daily dosing regimen.

  DOI：

  10.1021/acs.jmedchem.9b00720

文献信息

• From Phenylthiazoles to Phenylpyrazoles: Broadening the Antibacterial Spectrum toward Carbapenem-Resistant Bacteria
  作者：Ali Hammad、Nader S. Abutaleb、Mohamed M. Elsebaei、Allison B. Norvil、Mohamed Alswah、Alsagher O. Ali、Jelan A. Abdel-Aleem、Abdelaziz Alattar、Sammar A. Bayoumi、Humaira Gowher、Mohamed N. Seleem、Abdelrahman S. Mayhoub

  DOI：10.1021/acs.jmedchem.9b00720

  日期：2019.9.12

  The narrow antibacterial spectrum of phenylthiazole antibiotics was expanded by replacing central thiazole with a pyrazole ring while maintaining its other pharmacophoric features. The most promising derivative, compound 23, was more potent than vancomycin against multidrug-resistant Gram-positive clinical isolates, including vancomycin- and linezolid-resistant methicillin-resistant Staphylococcus aureus (MRSA), with a minimum inhibitory concentration (MIC) value as low as 0.5 mu g/mL. Moreover, compound 23 was superior to imipenem and meropenem against highly pathogenic carbapenem-resistant strains, such as Acinetobacter baumannii, Klebsiella pneumoniae, and Escherichia coli. In addition to the notable biofilm inhibition activity, compound 23 outperformed both vancomycin and kanamycin in reducing the intracellular burden of both Gram-positive and Gram-negative pathogenic bacteria. Compound 23 cleared 90% of intracellular MRSA and 98% of Salmonella enteritidis at 2X the MIC. Moreover, preliminary pharmacokinetic investigations indicated that this class of novel antibacterial compounds is highly metabolically stable with a biological half-life of 10.5 h, suggesting a once-daily dosing regimen.