2-amino-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxylic acid (4-fluorophenyl)amide

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 2-amino-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxylic acid (4-fluorophenyl)amide
• 英文别名: 2-amino-N-(4-fluorophenyl)-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxamide
• 化学式: C₁₆H₁₇FN₂OS
• 分子量: 304.388
• InChiKey: VNGHZKQZNWNKIS-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  21
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  83.4
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  2-amino-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxylic acid (4-fluorophenyl)amide 在 吡啶 、 三溴化硼 作用下， 以 二氯甲烷 为溶剂， 生成 N-(4-fluorophenyl)-2-(2-hydroxybenzamido)-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxamide
  参考文献：
  名称：

  Exploring the cycloheptathiophene-3-carboxamide scaffold to disrupt the interactions of the influenza polymerase subunits and obtain potent anti-influenza activity

  摘要：

  With the aim to identify small molecules able to disrupt PA-PB1 subunits interaction of influenza virus (flu) RNA-dependent RNA polymerase, and based on previous structural and computational information, in this paper we have designed and synthesized a new series of cycloheptathiophene-3-carboxamide (cHTC) derivatives. Their biological evaluation led to highlight important structural insights along with new interesting compounds, such as the 2-hydroxybenzamido derivatives 29, 31, and 32, and the 4-aminophenyl derivative 54, which inhibited viral growth in the low micromolar range (EC50 = 0.18 -1.2 mu M) at no toxic concentrations (CC50 > 250 mu M).This study permitted to obtain among the most potent anti-flu compounds within the PA-PB1 interaction inhibitors, confirming the cHTC scaffold as particularly suitable to achieve innovative anti-flu agents. (C) 2017 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2017.06.015
• 作为产物：
  描述：

  2-氰基-4'-氟乙酰苯胺 在 吗啉 、 1,2,3,4,5,6,7,8-八硫杂环辛烷 、 ammonium acetate 、 溶剂黄146 、 sodium sulfate 作用下， 以 乙醇 为溶剂， 反应 6.0h， 生成 2-amino-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxylic acid (4-fluorophenyl)amide
  参考文献：
  名称：

  Substituted 2-Acylaminocycloalkylthiophene-3-carboxylic Acid Arylamides as Inhibitors of the Calcium-Activated Chloride Channel Transmembrane Protein 16A (TMEM16A)

  摘要：

  Transmembrane protein 16A (TMEM16A), also called anoctamin 1 (ANO1), is a calcium-activated chloride channel expressed widely mammalian cells, including epithelia, vascular smooth muscle tissue, electrically excitable cells, and some tumors. TMEM16A inhibitors have been proposed for treatment of disorders of epithelial fluid and mucus secretion, hypertension, asthma, and possibly cancer. Herein we report, by screening, the discovery of 2-acylaminocycloalkylthiophene-3-carboxylic acid arylamides (AACTs) as inhibitors of TMEM16A and analysis of 48 synthesized analogs (10ab-10bw) of the original AACT compound (10aa). Structure activity studies indicated the importance of benzene substituted as 2- or 4-methyl, or 4-fluoro, and defined the significance of thiophene substituents and size of the cycloalkylthiophene core. The most potent compound (10bm), which contains an unusual bromodifluoroacetamide at the thiophene 2-position, had IC50 of similar to 30 nM, similar to 3.6-fold more potent than the most potent previously reported TMEM16A inhibitor 4 (Ani9), and >10-fold improved metabolic stability. Direct and reversible inhibition of TMEM16A by 10bm was demonstrated by patch-clamp analysis. AACTs may be useful as pharmacological tools to study TMEM16A function and as potential drug development candidates.

  DOI：

  10.1021/acs.jmedchem.7b00020

文献信息

• Optimization of 2-Acylaminocycloalkylthiophene Derivatives for Activity against Staphylococcus aureus RnpA
  作者：Michaelle Chojnacki、Xufeng Cao、Daniel P. Flaherty、Paul M. Dunman

  DOI：10.3390/antibiotics10040369

  日期：——

  Staphylococcus aureus is well-recognized to cause debilitating bacterial infections that are difficult to treat due to the emergence of antibiotic resistance. As such, there is a need to develop new antimicrobials for the therapeutic intervention of S. aureus disease. To that end, S. aureus RnpA is an essential enzyme that is hypothesized to participate in two required cellular processes, precursor tRNA (ptRNA) maturation and mRNA degradation. Corresponding high throughput screening campaigns have identified the phenylcarbamoyl cyclic thiopenes as a chemical class of RnpA inhibitors that display promising antibacterial effects by reducing RnpA ptRNA and mRNA degradation activities and low human cell toxicity. Herein, we perform a structure activity relationship study of the chemical scaffold. Results revealed that the cycloalkane ring size and trifluoroacetamide moiety are required for antibacterial activity, whereas modifications of the para and/or meta positions of the pharmacophore’s phenyl group allowed tuning of the scaffold’s antimicrobial performance and RnpA inhibitory activity. The top performing compounds with respect to antimicrobial activity also did not exhibit cytotoxicity to human cell lines at concentrations up to 100 µM, greater than 100-fold the minimum inhibitory concentration (MIC). Focused studies of one analog, RNP0012, which exhibited the most potent antimicrobial and inhibition of cellular RnpA activities revealed that the compound reduced bacterial burden in a murine model of S. aureus disease. Taken together, the results presented are expected to provide an early framework for optimization of next-generation of RnpA inhibitor analogues that may represent progenitors of a new class of antimicrobials.

  金黄色葡萄球菌被广泛认为会引起难以治疗的细菌感染，因为抗生素耐药性的出现。因此，有必要开发新的抗菌药物来治疗金黄色葡萄球菌疾病。为此，金黄色葡萄球菌RnpA是一种必不可少的酶，据推测参与两个必需的细胞过程，前体tRNA（ptRNA）成熟和mRNA降解。相应的高通量筛选活动已经确定苯基氨基环硫烯为一种RnpA抑制剂的化学类，通过降低RnpA ptRNA和mRNA降解活性以及低人类细胞毒性显示出有希望的抗菌效果。在这里，我们进行了化学骨架的结构活性关系研究。结果显示，环烷烃环大小和三氟乙酰胺基团对抗菌活性是必需的，而对药效团苯基的对位和/或间位的修饰允许调节骨架的抗微生物性能和RnpA抑制活性。在抗微生物活性方面表现最佳的化合物在浓度高达100 µM时也没有对人类细胞系表现出细胞毒性，这比最低抑菌浓度（MIC）高出100倍。对一种类似物RNP0012的重点研究显示，该化合物减少了在金黄色葡萄球菌疾病小鼠模型中的细菌负担。综合而言，所呈现的结果预计将为优化下一代RnpA抑制剂类似物的早期框架提供基础，这些类似物可能代表新一类抗菌药物的前体。