1,4-bis{6-[ethoxy(imino)methyl]indol-2-yl}benzene hydrochloric acid salt

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: 1,4-bis{6-[ethoxy(imino)methyl]indol-2-yl}benzene hydrochloric acid salt
• 英文别名: ethyl 2-[4-[6-(C-ethoxycarbonimidoyl)-1H-indol-2-yl]phenyl]-1H-indole-6-carboximidate;hydrochloride
• 化学式: C₂₈H₂₆N₄O₂*(x)ClH
• 分子量: 487.0
• InChiKey: VYRDVNGDXYQQSW-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.13
• 重原子数：
  35
• 可旋转键数：
  8
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.14
• 拓扑面积：
  97.7
• 氢给体数：
  5
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  1,4-bis{6-[ethoxy(imino)methyl]indol-2-yl}benzene hydrochloric acid salt 在 氨 作用下， 以 乙醇 为溶剂， 生成 2-[4-(6-carbamimidoyl-1H-indol-2-yl)phenyl]-1H-indole-6-carboximidamide;hydrochloride
  参考文献：
  名称：

  Synthesis and antifungal evaluation of head-to-head and head-to-tail bisamidine compounds

  摘要：

  Herein, we describe the antifungal evaluation of 43 bisamidine compounds, of which 26 are new, having the scaffold [Am]-[HetAr]-[linker]-[HetAr]-[Am], in which [Am] is a cyclic or acyclic amidine group, [linker] is a benzene, pyridine, pyrimidine, pyrazine ring, or an aliphatic chain of two to four carbon, and [HetAr] is a 5,6-bicyclic heterocycle such as indole, benzimidazole, imidazopyridine, benzofuran, or benzothiophene. In the head-to-head series the two [HetAr] units are oriented such that the 5-membered rings are connected through the linker, and in the head-to-tail series, one of the [HetAr] systems is connected through the 6-membered ring; additionally, in some of the head-to-tail compounds, the [linker] is omitted. Many of these compounds exhibited significant antifungal activity against Candida albicans, Candida krusei, Candida glabrata, Candida parapsilosis, and Cryptococcus neoformans (MIC <= 4 mu g/ml). The most potent compounds, for example, P10, P19 and P34, are comparable in antifungal activities to amphotericin B (MIC 0.125 mu g/ml). They exhibited rapid fungicidal activity (>3 log(10) decrease in cfu/ml in 4 h) at concentrations equivalent to 4x the MIC in time kill experiments. The bisamidines strongly inhibited DNA, RNA and cell wall biosynthesis in C. albicans in macromolecular synthesis assays. However, the half-maximal inhibitory concentration for DNA synthesis was approximately 30-fold lower than those for RNA and cell wall biosynthesis. Fluorescence microscopy of intact cells of C. albicans treated with a bisamidine exhibited enhanced fluorescence in the presence of DNA, demonstrating that the bisamidine was localized to the nucleus. The results of this study show that bisamidines are potent antifungal agents with rapid fungicidal activity, which is likely to be the result of their DNA-binding activity. Although it was difficult to obtain a broad-spectrum antifungal compound with low cytotoxicity, some of the compounds (e.g., P9, P14 and P43) exhibited favorable CC50 values against HeLa cells and maintained considerable antifungal activity. (C) 2015 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2015.07.006
• 作为产物：
  描述：

  4-甲基-3-硝基苯甲腈 在 哌啶 、 环丁砜 、 盐酸 作用下， 反应 168.75h， 生成 1,4-bis{6-[ethoxy(imino)methyl]indol-2-yl}benzene hydrochloric acid salt
  参考文献：
  名称：

  Synthesis and structure-activity relationship of novel bisindole amidines active against MDR Gram-positive and Gram-negative bacteria

  摘要：

  A series of novel diamidines with N-substituents on an amidine N-atom were synthesized and evaluated for their cytotoxicity and in vitro antibacterial activity against a range of Gram-positive and Gram-negative bacterial strains. Based on structure-activity relationship, N-substituents with a branched chain and a shorter carbon chain on the amidine N-atom exhibited more promising activity against Gram-negative and MDR-Gram-positive bacteria: compounds 5c and Si were the most powerful candidate compounds. Compound 5c showed greater efficacy than levofloxacin against most drug resistant Gram-positive bacteria and exhibited broad-spectrum antibacterial activity against Gram-negative bacteria, with MIC values in the range of 2-16 mu g/mL. Slightly more potent antibacterial activity against Klebsiella pneumoniae, Acinetobacter calcoaceticus, Enterobacter cloacae, and Proteus mirabilis was observed for 5i in comparison with 5c. Compound 5i also showed remarkable antibacterial activity against NDM-1-producing Gram-negative bacteria, with MIC values in the range of 2-4 mu g/mL, and was superior to the reference drugs meropenem and levofloxacin. Effective antibacterial activity of 5i was also shown in vivo in a mouse model of Staphylococcus aureus MRSA strain, with an ED(50)values of 2.62 mg/kg. (C) 2018 Published by Elsevier Masson SAS.

  DOI：

  10.1016/j.ejmech.2018.03.031

文献信息

• Potent and broad-spectrum antibacterial activity of indole-based bisamidine antibiotics: Synthesis and SAR of novel analogs of MBX 1066 and MBX 1090
  作者：John D. Williams、Son T. Nguyen、Shen Gu、Xiaoyuan Ding、Michelle M. Butler、Tommy F. Tashjian、Timothy J. Opperman、Rekha G. Panchal、Sina Bavari、Norton P. Peet、Donald T. Moir、Terry L. Bowlin

  DOI：10.1016/j.bmc.2013.10.014

  日期：2013.12

  The prevalence of drug-resistant bacteria in the clinic has propelled a concerted effort to find new classes of antibiotics that will circumvent current modes of resistance. We have previously described a set of bisamidine antibiotics that contains a core composed of two indoles and a central linker. The first compounds of the series, MBX 1066 and MBX 1090, have potent antibacterial properties against a wide range of Gram-positive and Gram-negative bacteria. We have conducted a systematic exploration of the amidine functionalities, the central linker, and substituents at the indole 3-position to determine the factors involved in potent antibacterial activity. Some of the newly synthesized compounds have even more potent and broad-spectrum activity than MBX 1066 and MBX 1090. (C) 2013 Elsevier Ltd. All rights reserved.
• Synthesis and structure-activity relationship of novel bisindole amidines active against MDR Gram-positive and Gram-negative bacteria
  作者：Yonghua Liu、Xinxin Hu、Yanbin Wu、Weixing Zhang、Xiaofang Chen、Xuefu You、Laixing Hu

  DOI：10.1016/j.ejmech.2018.03.031

  日期：2018.4

  A series of novel diamidines with N-substituents on an amidine N-atom were synthesized and evaluated for their cytotoxicity and in vitro antibacterial activity against a range of Gram-positive and Gram-negative bacterial strains. Based on structure-activity relationship, N-substituents with a branched chain and a shorter carbon chain on the amidine N-atom exhibited more promising activity against Gram-negative and MDR-Gram-positive bacteria: compounds 5c and Si were the most powerful candidate compounds. Compound 5c showed greater efficacy than levofloxacin against most drug resistant Gram-positive bacteria and exhibited broad-spectrum antibacterial activity against Gram-negative bacteria, with MIC values in the range of 2-16 mu g/mL. Slightly more potent antibacterial activity against Klebsiella pneumoniae, Acinetobacter calcoaceticus, Enterobacter cloacae, and Proteus mirabilis was observed for 5i in comparison with 5c. Compound 5i also showed remarkable antibacterial activity against NDM-1-producing Gram-negative bacteria, with MIC values in the range of 2-4 mu g/mL, and was superior to the reference drugs meropenem and levofloxacin. Effective antibacterial activity of 5i was also shown in vivo in a mouse model of Staphylococcus aureus MRSA strain, with an ED(50)values of 2.62 mg/kg. (C) 2018 Published by Elsevier Masson SAS.
• Synthesis and antifungal evaluation of head-to-head and head-to-tail bisamidine compounds
  作者：Son T. Nguyen、Steven M. Kwasny、Xiaoyuan Ding、John D. Williams、Norton P. Peet、Terry L. Bowlin、Timothy J. Opperman

  DOI：10.1016/j.bmc.2015.07.006

  日期：2015.9

  Herein, we describe the antifungal evaluation of 43 bisamidine compounds, of which 26 are new, having the scaffold [Am]-[HetAr]-[linker]-[HetAr]-[Am], in which [Am] is a cyclic or acyclic amidine group, [linker] is a benzene, pyridine, pyrimidine, pyrazine ring, or an aliphatic chain of two to four carbon, and [HetAr] is a 5,6-bicyclic heterocycle such as indole, benzimidazole, imidazopyridine, benzofuran, or benzothiophene. In the head-to-head series the two [HetAr] units are oriented such that the 5-membered rings are connected through the linker, and in the head-to-tail series, one of the [HetAr] systems is connected through the 6-membered ring; additionally, in some of the head-to-tail compounds, the [linker] is omitted. Many of these compounds exhibited significant antifungal activity against Candida albicans, Candida krusei, Candida glabrata, Candida parapsilosis, and Cryptococcus neoformans (MIC <= 4 mu g/ml). The most potent compounds, for example, P10, P19 and P34, are comparable in antifungal activities to amphotericin B (MIC 0.125 mu g/ml). They exhibited rapid fungicidal activity (>3 log(10) decrease in cfu/ml in 4 h) at concentrations equivalent to 4x the MIC in time kill experiments. The bisamidines strongly inhibited DNA, RNA and cell wall biosynthesis in C. albicans in macromolecular synthesis assays. However, the half-maximal inhibitory concentration for DNA synthesis was approximately 30-fold lower than those for RNA and cell wall biosynthesis. Fluorescence microscopy of intact cells of C. albicans treated with a bisamidine exhibited enhanced fluorescence in the presence of DNA, demonstrating that the bisamidine was localized to the nucleus. The results of this study show that bisamidines are potent antifungal agents with rapid fungicidal activity, which is likely to be the result of their DNA-binding activity. Although it was difficult to obtain a broad-spectrum antifungal compound with low cytotoxicity, some of the compounds (e.g., P9, P14 and P43) exhibited favorable CC50 values against HeLa cells and maintained considerable antifungal activity. (C) 2015 Elsevier Ltd. All rights reserved.