2-amino-N-(2-pyridinyl)-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxamide | 1512843-48-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 环七噻吩
• 英文名称: 2-amino-N-(2-pyridinyl)-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxamide
• 英文别名: 2-amino-N-(2-pyridyl)-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxamide；2-amino-N-pyridin-2-yl-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxamide
• CAS: 1512843-48-9
• 化学式: C₁₅H₁₇N₃OS
• 分子量: 287.385
• InChiKey: FNVLKGWRMNTDKR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.25
• 重原子数：
  20.0
• 可旋转键数：
  2.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  68.01
• 氢给体数：
  2.0
• 氢受体数：
  4.0

反应信息

• 作为反应物：
  描述：

  2-amino-N-(2-pyridinyl)-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxamide 在 吡啶 、 palladium 10% on activated carbon 、 甲酸铵 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 140.0h， 生成 2-(2-aminobenzamido)-N-(pyridin-2-yl)-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxamide
  参考文献：
  名称：

  环庚基噻吩-3-羧酰胺衍生物作为变构HIV-1核糖核酸酶H抑制剂的研究

  摘要：

  尽管联合抗逆转录病毒疗法在抵抗人类免疫缺陷病毒（HIV）感染方面取得了显着进展，但根除该病毒的困难以及多药耐药菌株的迅速出现显然突显了对创新药物的迫切需求，可能拥有新颖的药物。作用机制。在这种情况下，由于其在HIV基因组复制中的重要作用，逆转录酶相关的核糖核酸酶H（RNase H）已被证明是有吸引力的目标。为了鉴定新的RNase H抑制剂，筛选了一个室内环庚噻吩-3-羧酰胺库。这导致具有抑制活性的化合物，其结构优化导致儿茶酚衍生物2-（3,4-dihydroxybenzamido）-N-（吡啶-2-基）-5,6,7,8-四氢-4 H-环庚[ b ]噻吩-3-羧酰胺（化合物33），其RNase H活性的IC 50值在纳摩尔范围内。机理研究表明，通过与创新的变构位点结合，选择性抑制RNase H，可以进一步利用它来丰富这类抑制剂。

  DOI：

  10.1002/cmdc.201600015
• 作为产物：
  描述：

  2-氰基-N-吡啶-2-基-乙酰胺 在 ammonium acetate 、 sulfur 、 溶剂黄146 、 二乙胺 作用下， 以 苯 为溶剂， 反应 17.5h， 生成 2-amino-N-(2-pyridinyl)-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxamide
  参考文献：
  名称：

  环庚基噻吩-3-羧酰胺衍生物作为变构HIV-1核糖核酸酶H抑制剂的研究

  摘要：

  尽管联合抗逆转录病毒疗法在抵抗人类免疫缺陷病毒（HIV）感染方面取得了显着进展，但根除该病毒的困难以及多药耐药菌株的迅速出现显然突显了对创新药物的迫切需求，可能拥有新颖的药物。作用机制。在这种情况下，由于其在HIV基因组复制中的重要作用，逆转录酶相关的核糖核酸酶H（RNase H）已被证明是有吸引力的目标。为了鉴定新的RNase H抑制剂，筛选了一个室内环庚噻吩-3-羧酰胺库。这导致具有抑制活性的化合物，其结构优化导致儿茶酚衍生物2-（3,4-dihydroxybenzamido）-N-（吡啶-2-基）-5,6,7,8-四氢-4 H-环庚[ b ]噻吩-3-羧酰胺（化合物33），其RNase H活性的IC 50值在纳摩尔范围内。机理研究表明，通过与创新的变构位点结合，选择性抑制RNase H，可以进一步利用它来丰富这类抑制剂。

  DOI：

  10.1002/cmdc.201600015

文献信息

• From cycloheptathiophene-3-carboxamide to oxazinone-based derivatives as allosteric HIV-1 ribonuclease H inhibitors
  作者：Serena Massari、Angela Corona、Simona Distinto、Jenny Desantis、Alessia Caredda、Stefano Sabatini、Giuseppe Manfroni、Tommaso Felicetti、Violetta Cecchetti、Christophe Pannecouque、Elias Maccioni、Enzo Tramontano、Oriana Tabarrini

  DOI：10.1080/14756366.2018.1523901

  日期：2019.1.1

  Abstract The paper focussed on a step-by-step structural modification of a cycloheptathiophene-3-carboxamide derivative recently identified by us as reverse transcriptase (RT)-associated ribonuclease H (RNase H) inhibitor. In particular, its conversion to a 2-aryl-cycloheptathienoozaxinone derivative and the successive thorough exploration of both 2-aromatic and cycloheptathieno moieties led to identify

  抽象的 本文重点研究了最近被我们鉴定为逆转录酶（RT）相关的核糖核酸酶H（RNase H）抑制剂的环庚噻吩-3-甲酰胺衍生物的逐步结构修饰。特别地，其向2-芳基-环庚硫基杂氮杂酮衍生物的转化以及对2-芳族和环庚二硫基部分的连续深入探索导致将基于恶嗪酮的化合物鉴定为新的抗RNA酶H化学型。支架C-2位置上邻苯二酚部分的出现对于实现有效的抗RNA酶H活性至关重要，该活性还包括三环衍生物的抗RNA依赖性DNA聚合酶（RDDP）活性。苯并噻吩并恶嗪酮衍生物22产生的最强双重抑制剂表现出IC 50相对于RNase H和RDDP功能的s分别为0.53和2.90μM。诱变和对接研究表明，化合物22结合了RT中的两个变构口袋，一个位于RNase H活性位点和引物结合区之间，另一个位于DNA聚合酶催化中心附近。
• Synthesis and characterization of 1,2,4-triazolo[1,5-a]pyrimidine-2-carboxamide-based compounds targeting the PA-PB1 interface of influenza A virus polymerase
  作者：Serena Massari、Chiara Bertagnin、Maria Chiara Pismataro、Anna Donnadio、Giulio Nannetti、Tommaso Felicetti、Stefano Di Bona、Maria Giulia Nizi、Leonardo Tensi、Giuseppe Manfroni、Maria Isabel Loza、Stefano Sabatini、Violetta Cecchetti、Jose Brea、Laura Goracci、Arianna Loregian、Oriana Tabarrini

  DOI：10.1016/j.ejmech.2020.112944

  日期：2021.1

  Influenza viruses (Flu) are responsible for seasonal epidemics causing high rates of morbidity, which can dramatically increase during severe pandemic outbreaks. Antiviral drugs are an indispensable weapon to treat infected people and reduce the impact on human health, nevertheless anti-Flu armamentarium still remains inadequate. In search for new anti-Flu drugs, our group has focused on viral RNA-dependent RNA polymerase (RdRP) developing disruptors of PA-PB1 subunits interface with the best compounds characterized by cycloheptathiophene-3-carboxamide and 1,2,4-triazolo[1,5-a]pyrimidine-2-carboxamide scaffolds. By merging these moieties, two very interesting hybrid compounds were recently identified, starting from which, in this paper, a series of analogues were designed and synthesized. In particular, a thorough exploration of the cycloheptathiophene-3-carboxamide moiety led to acquire important SAR insight and identify new active compounds showing both the ability to inhibit PA-PB1 interaction and viral replication in the micromolar range and at non-toxic concentrations. For few compounds, the ability to efficiently inhibit PA-PB1 subunits interaction did not translate into anti-Flu activity. Chemical/physical properties were investigated for a couple of compounds suggesting that the low solubility of compound 14, due to a strong crystal lattice, may have impaired its antiviral activity. Finally, computational studies performed on compound 23, in which the phenyl ring suitably replaced the cycloheptathiophene, suggested that, in addition to hydrophobic interactions, H-bonds enhanced its binding within the PAC cavity.
• Exploring the cycloheptathiophene-3-carboxamide scaffold to disrupt the interactions of the influenza polymerase subunits and obtain potent anti-influenza activity
  作者：Jenny Desantis、Giulio Nannetti、Serena Massari、Maria Letizia Barreca、Giuseppe Manfroni、Violetta Cecchetti、Giorgio Palù、Laura Goracci、Arianna Loregian、Oriana Tabarrini

  DOI：10.1016/j.ejmech.2017.06.015

  日期：2017.9

  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.
• Structural Investigation of Cycloheptathiophene-3-carboxamide Derivatives Targeting Influenza Virus Polymerase Assembly
  作者：Serena Massari、Giulio Nannetti、Laura Goracci、Luca Sancineto、Giulia Muratore、Stefano Sabatini、Giuseppe Manfroni、Beatrice Mercorelli、Violetta Cecchetti、Marzia Facchini、Giorgio Palù、Gabriele Cruciani、Arianna Loregian、Oriana Tabarrini

  DOI：10.1021/jm401560v

  日期：2013.12.27

  The limited number of drug classes licensed for treatment of influenza virus (Flu), together with the continuous emergence of viral variants and drug resistant mutants, highlights the urgent need to find antivirals with novel mechanisms of action. In this context, the viral RNA-dependent RNA polymerase (RdRP) subunits assembly has emerged as an attractive target. Starting from a cycloheptathiophene-3-carboxamide derivative recently identified by us for its ability to disrupt the interaction between the PA and PB1 subunits of RdRP, we have designed and synthesized a series of analogues. Their biological evaluation led to the identification of more potent protein protein interaction inhibitors, endowed with antiviral activity that also encompassed a number of clinical isolates of FluA, including an oseltamivir-resistant strain, and FluB, without showing appreciable toxicity. From this study, the cycloheptathiophene-3-carboxamide scaffold emerged as being particularly suitable to impart anti-Flu activity.
• Studies on Cycloheptathiophene-3-carboxamide Derivatives as Allosteric HIV-1 Ribonuclease H Inhibitors
  作者：Angela Corona、Jenny Desantis、Serena Massari、Simona Distinto、Takashi Masaoka、Stefano Sabatini、Francesca Esposito、Giuseppe Manfroni、Elias Maccioni、Violetta Cecchetti、Christophe Pannecouque、Stuart F. J. Le Grice、Enzo Tramontano、Oriana Tabarrini

  DOI：10.1002/cmdc.201600015

  日期：2016.8.19

  immunodeficiency virus (HIV) infection, the difficulty to eradicate the virus together with the rapid emergence of multidrug‐resistant strains clearly underline a pressing need for innovative agents, possibly endowed with novel mechanisms of action. In this context, owing to its essential role in HIV genome replication, the reverse transcriptase associated ribonuclease H (RNase H) has proven to be an

  尽管联合抗逆转录病毒疗法在抵抗人类免疫缺陷病毒（HIV）感染方面取得了显着进展，但根除该病毒的困难以及多药耐药菌株的迅速出现显然突显了对创新药物的迫切需求，可能拥有新颖的药物。作用机制。在这种情况下，由于其在HIV基因组复制中的重要作用，逆转录酶相关的核糖核酸酶H（RNase H）已被证明是有吸引力的目标。为了鉴定新的RNase H抑制剂，筛选了一个室内环庚噻吩-3-羧酰胺库。这导致具有抑制活性的化合物，其结构优化导致儿茶酚衍生物2-（3,4-dihydroxybenzamido）-N-（吡啶-2-基）-5,6,7,8-四氢-4 H-环庚[ b ]噻吩-3-羧酰胺（化合物33），其RNase H活性的IC 50值在纳摩尔范围内。机理研究表明，通过与创新的变构位点结合，选择性抑制RNase H，可以进一步利用它来丰富这类抑制剂。