benzyl (4-(4-bromophenyl)-1H-imidazol-2-yl)methylcarbamate | 945473-55-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: benzyl (4-(4-bromophenyl)-1H-imidazol-2-yl)methylcarbamate
• 英文别名: benzyl ((5-(4-bromophenyl)-1H-imidazol-2-yl)methyl)carbamate；benzyl N-[[5-(4-bromophenyl)-1H-imidazol-2-yl]methyl]carbamate
• CAS: 945473-55-2
• 化学式: C₁₈H₁₆BrN₃O₂
• 分子量: 386.248
• InChiKey: NZMIAQXKYLDAEV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  24
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.11
• 拓扑面积：
  67
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  benzyl (4-(4-bromophenyl)-1H-imidazol-2-yl)methylcarbamate 在 盐酸 、 N,N-二异丙基乙胺 作用下， 以 1,4-二氧六环 、 N,N-二甲基甲酰胺 为溶剂， 反应 18.0h， 生成 1-(4-(1H-imidazol-4-yl)phenyl)-3-((5-(4-bromophenyl)-1H-imidazol-2-yl)methyl)urea
  参考文献：
  名称：

  靶向结核分枝杆菌肌苷 5'-单磷酸脱氢酶 (IMPDH) 的基于片段的方法。

  摘要：

  结核病 (TB) 仍然是全世界死亡的主要原因，需要改进治疗以对抗耐药性的出现。肌苷 5'-单磷酸脱氢酶 (IMPDH) 是从头合成鸟嘌呤核苷酸所需的关键酶，是一种有吸引力的结核病药物靶点。在这里，我们描述了使用基于片段的筛选和基于结构的设计技术来鉴定有效的 IMPDH 抑制剂。筛选耐热分枝杆菌 (Mth) IMPDH ΔCBS 抑制剂的片段库确定了一种低亲和力苯基咪唑衍生物。第 M 个 IMPDH ΔCBS-IMP-抑制剂复合物的 X 射线晶体学显示该片段的两个分子结合在 IMPDH 的 NAD 结合口袋中。

  DOI：

  10.1021/acs.jmedchem.7b01622
• 作为产物：
  描述：

  N-苄氧羰基氨基乙腈 在 sodium methylate 、 potassium carbonate 作用下， 以 四氢呋喃 、 甲醇 、 水 为溶剂， 反应 98.0h， 生成 benzyl (4-(4-bromophenyl)-1H-imidazol-2-yl)methylcarbamate
  参考文献：
  名称：

  Small-Molecule Inhibition of the C. difficile FAS-II Enzyme, FabK, Results in Selective Activity

  摘要：

  Clostridioides difficile infection (CDI) is a leading cause of significant morbidity, mortality, and healthcare-related costs in the United States. After standard therapy, recurrence rates remain high, and multiple recurrences are not uncommon. Causes include treatments employing broad-spectrum agents that disrupt the normal host microbiota, as well as treatment-resistant spore formation by C. difficile. Thus, novel druggable anti-C. difficile targets that promote narrow-spectrum eradication and inhibition of sporulation are desired. As a critical rate-limiting step within the FAS-II bacterial fatty acid synthesis pathway, which supplies precursory component phospholipids found in bacterial cytoplasmic and spore-mediated membranes, enoyl-acyl carrier protein (ACP) reductase II (FabK) represents such a target. FabK is essential in C. difficile (CdFabK) and is structurally and mechanistically distinct from other isozymes found in gut microbiota species, making CdFabK an attractive narrow-spectrum target. We report here the kinetic evaluation of CdFabK, the biochemical activity of a series of phenylimidazole analogues, and microbiological data suggesting these compounds' selective antibacterial activity against C. difficile versus several other prominent gut organisms. The compounds display promising, selective, low micromolar CdFabK inhibitory activity without significantly affecting the growth of other gut organisms, and the series prototype (1b) is shown to be competitive for the CdFabK cofactor and uncompetitive for the substrate. A series analogue (1g) shows maintained inhibitory activity while also possessing increased solubility. These findings represent the basis for future drug discovery efforts by characterizing the CdFabK enzyme while demonstrating its druggability and potential role as a narrow-spectrum antidifficile target.

  DOI：

  10.1021/acschembio.9b00293

文献信息

• Phenylimidazole Derivatives of 4-Pyridone as Dual Inhibitors of Bacterial Enoyl-Acyl Carrier Protein Reductases FabI and FabK
  作者：Hideo Kitagawa、Tomohiro Ozawa、Sho Takahata、Maiko Iida、Jun Saito、Mototsugu Yamada

  DOI：10.1021/jm0705354

  日期：2007.9.1

  reductases that catalyze the final and rate-limiting step of bacterial fatty acid biosynthesis (FAS) and are potential targets of novel antibacterial agents. We have reported 4-pyridone derivative 3 as a FabI inhibitor and phenylimidazole derivative 5 as a FabK inhibitor. Here, we will report phenylimidazole derivatives of 4-pyridone as FabI and FabK dual inhibitors based on an iterative medicinal chemistry

  FabI和FabK是细菌烯酰酰基载体蛋白（ACP）还原酶，可催化细菌脂肪酸生物合成（FAS）的最终步骤和限速步骤，并且是新型抗菌剂的潜在靶标。我们已经报道了4-吡啶酮衍生物3作为FabI抑制剂，而苯基咪唑衍生物5作为FabK抑制剂。在此，我们将基于肺炎链球菌/化合物26的FabK的迭代药物化学和结晶学研究，报告4-吡啶酮的苯基咪唑衍生物作为FabI和FabK双重抑制剂。代表性化合物6具有较强的FabI抑制作用（IC50 = 0.38 microM），并且FabK抑制性活性（IC50 = 0.0045 microM），对肺炎链球菌有很强的抗菌活性（MIC = 0.5 microg / mL）。由于观察到针对S的MIC值升高。在FabK中具有一个氨基酸取代的肺炎突变体，该化合物的抗菌活性被认为是由于对FabK的抑制。此外，该化合物未显示明显的细胞毒性（IC50> 69 microM）。这些结果
• Phenylimidazole derivatives as specific inhibitors of bacterial enoyl-acyl carrier protein reductase FabK
  作者：Tomohiro Ozawa、Hideo Kitagawa、Yasuo Yamamoto、Sho Takahata、Maiko Iida、Yumi Osaki、Keiko Yamada

  DOI：10.1016/j.bmc.2007.08.050

  日期：2007.12

  Bacterial enoyl-acyl carrier protein (ACP) reductases (FabI and FabK) catalyze the final step in each cycle of bacterial fatty acid biosynthesis and are attractive targets for the development of new antibacterial agents. Here, we report the development of novel FabK inhibitors with antibacterial activity against Streptococcus pneumoniae. Based on structure-activity relationship (SAR) studies of our screening hits, we have developed novel phenylimidazole derivatives as potent FabK inhibitors. (C) 2007 Elsevier Ltd. All rights reserved.
• Small-Molecule Inhibition of the <i>C. difficile</i> FAS-II Enzyme, FabK, Results in Selective Activity
  作者：Jesse A. Jones、Allan M. Prior、Ravi K. R. Marreddy、Rebecca D. Wahrmund、Julian G. Hurdle、Dianqing Sun、Kirk E. Hevener

  DOI：10.1021/acschembio.9b00293

  日期：2019.7.19

  Clostridioides difficile infection (CDI) is a leading cause of significant morbidity, mortality, and healthcare-related costs in the United States. After standard therapy, recurrence rates remain high, and multiple recurrences are not uncommon. Causes include treatments employing broad-spectrum agents that disrupt the normal host microbiota, as well as treatment-resistant spore formation by C. difficile. Thus, novel druggable anti-C. difficile targets that promote narrow-spectrum eradication and inhibition of sporulation are desired. As a critical rate-limiting step within the FAS-II bacterial fatty acid synthesis pathway, which supplies precursory component phospholipids found in bacterial cytoplasmic and spore-mediated membranes, enoyl-acyl carrier protein (ACP) reductase II (FabK) represents such a target. FabK is essential in C. difficile (CdFabK) and is structurally and mechanistically distinct from other isozymes found in gut microbiota species, making CdFabK an attractive narrow-spectrum target. We report here the kinetic evaluation of CdFabK, the biochemical activity of a series of phenylimidazole analogues, and microbiological data suggesting these compounds' selective antibacterial activity against C. difficile versus several other prominent gut organisms. The compounds display promising, selective, low micromolar CdFabK inhibitory activity without significantly affecting the growth of other gut organisms, and the series prototype (1b) is shown to be competitive for the CdFabK cofactor and uncompetitive for the substrate. A series analogue (1g) shows maintained inhibitory activity while also possessing increased solubility. These findings represent the basis for future drug discovery efforts by characterizing the CdFabK enzyme while demonstrating its druggability and potential role as a narrow-spectrum antidifficile target.
• Fragment-Based Approach to Targeting Inosine-5′-monophosphate Dehydrogenase (IMPDH) from <i>Mycobacterium tuberculosis</i>
  作者：Ana Trapero、Angela Pacitto、Vinayak Singh、Mohamad Sabbah、Anthony G. Coyne、Valerie Mizrahi、Tom L. Blundell、David B. Ascher、Chris Abell

  DOI：10.1021/acs.jmedchem.7b01622

  日期：2018.4.12

  dehydrogenase (IMPDH), a crucial enzyme required for de novo synthesis of guanine nucleotides, is an attractive TB drug target. Herein, we describe the identification of potent IMPDH inhibitors using fragment-based screening and structure-based design techniques. Screening of a fragment library for Mycobacterium thermoresistible ( Mth) IMPDH ΔCBS inhibitors identified a low affinity phenylimidazole derivative

  结核病 (TB) 仍然是全世界死亡的主要原因，需要改进治疗以对抗耐药性的出现。肌苷 5'-单磷酸脱氢酶 (IMPDH) 是从头合成鸟嘌呤核苷酸所需的关键酶，是一种有吸引力的结核病药物靶点。在这里，我们描述了使用基于片段的筛选和基于结构的设计技术来鉴定有效的 IMPDH 抑制剂。筛选耐热分枝杆菌 (Mth) IMPDH ΔCBS 抑制剂的片段库确定了一种低亲和力苯基咪唑衍生物。第 M 个 IMPDH ΔCBS-IMP-抑制剂复合物的 X 射线晶体学显示该片段的两个分子结合在 IMPDH 的 NAD 结合口袋中。