2-amino-4-methyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide | 691396-95-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 噻吩类
• 英文名称: 2-amino-4-methyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide
• 英文别名: 2-Amino-4-methyl-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide
• CAS: 691396-95-9
• 化学式: C₁₀H₁₄N₂OS
• 分子量: 210.3
• InChiKey: YUJDMCQEVFLVLZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  14
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  97.4
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  2-amino-4-methyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide 、 2-硝基苯甲酰氯 在 吡啶 作用下， 反应 16.0h， 生成 tetrahydrobenzothiophene (THBT), 17
  参考文献：
  名称：

  Identification of PDE4B Over 4D subtype-selective inhibitors revealing an unprecedented binding mode

  摘要：

  A PDE4B over 4D-selective inhibitor programme was initiated to capitalise on the recently discovered predominance of the PDE4B subtype in inflammatory cell regulation. The SAR of a tetrahydrobenzothiophene (THBT) series did not agree with either of two proposed docking modes in the 4B binding site. A subsequent X-ray co- crystal structure determination revealed that the THBT ligand displaces the Gln-443 residue, invariably ligand-anchoring in previous PDE4 co-crystal structures, and even shifts helix-15 by 1-2 angstrom. For the first time, several residues of the C-terminus previously proposed to be involved in subtype selectivity are resolved and three of them extend into the ligand binding site potentially allowing for selective drug design. (C) 2009 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2009.03.061
• 作为产物：
  描述：

  2-甲基环己酮 、 氰乙酰胺 在 吗啉 、 sulfur 作用下， 反应 48.0h， 以17%的产率得到2-amino-4-methyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide
  参考文献：
  名称：

  Discovery, structure-activity relationship study and biological evaluation of 2-thioureidothiophene-3-carboxylates as a novel class of C-X-C chemokine receptor 2 (CXCR2) antagonists

  摘要：

  The C-X-C motif ligand 8 and C-X-C chemokine receptor 2 (CXCL8-CXCR2) axis is involved in pathogenesis of various diseases including inflammation and cancers. Various CXCR2 antagonists are under development for several diseases. Our previous high-throughput cell-based assay specific for CXCR2 has identified a pyrimidine-based compound CX797 acting on CXCR2 down-stream signaling. A lead optimization campaign through scaffold-hopping strategy led to a series of 2-thioureidothiophene-3-carboxylates (TUTP) as novel CXCR2 antagonists. Structure-activity relationship study of TUTPs led to the identification of compound 52 that significantly inhibited CXCR2-mediated beta-arrestin recruitment signaling (IC50 = 1.1 +/- 0.01 mu M) with negligible effect on CXCL8-mediated cAMP signaling and calcium flux. Similar to the known CXCR2 antagonist SB265610, compound 52 inhibited CXCL8-CXCR2 induced phosphorylation of ERK1/2. TUTP compounds also inhibited CXCL8-mediated cell migration and showed synergy with doxorubicin in ovarian cancer cells, thereby supporting TUTPs as promising compounds for cancer treatment. (C) 2020 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2020.112387

文献信息

• Dihydroxyphenyl- and Heteroaromatic-Based Thienopyrimidinones to Tackle HIV-1 LEDGF/p75-Dependent IN Activity
  作者：Graziella Tocco、Serena Canton、Antonio Laus、Pierluigi Caboni、Stuart F. J. Le Grice、Enzo Tramontano、Francesca Esposito

  DOI：10.3390/molecules28186700

  日期：——

  The spread of Human Immunodeficiency Virus (HIV) still represents a global public health issue of major concern, and would benefit from unveiling unique viral features as targets for drug design. In this respect, HIV-1 integrase (IN), due to the absence of homologs in human cells, is a popular target for the synthesis of novel selective compounds. Moreover, as drug-resistant viral strains are rapidly evolving, the development of novel allosteric inhibitors is acutely required. Recently, we have observed that Kuwanon-L, quinazolinones and thienopyrimidinones containing at least one polyphenol unit, effectively inhibited HIV-1 IN activity. Thus, in the present research, novel dihydroxyphenyl-based thienopyrimidinone derivatives were investigated for their LEDGF/p75-dependent IN inhibitory activity. Our findings indicated a close correlation between the position of the OH group on the phenyl moiety and IN inhibitory activity of these compounds. As catechol may be involved in cytotoxicity, its replacement by other aromatic scaffolds was also exploited. As a result, compounds 21–23, 25 and 26 with enhanced IN inhibitory activity provided good lead candidates, with 25 being the most selective for IN. Lastly, UV spectrometric experiments suggested a plausible allosteric mode of action, as none of the thienopirimidinones showed Mg2+ chelation properties otherwise typical of IN strand transfer inhibitors (INSTIs).

  人类免疫缺陷病毒（HIV）的传播仍然是一个令人严重关切的全球公共卫生问题，揭示病毒的独特特征作为药物设计的靶点将使我们受益匪浅。在这方面，HIV-1 整合酶（IN）由于在人类细胞中没有同源物，是合成新型选择性化合物的热门靶点。此外，随着耐药病毒株的迅速发展，新型异构抑制剂的开发迫在眉睫。最近，我们观察到含有至少一个多酚单元的 Kuwanon-L、喹唑啉酮类和噻吩嘧啶酮类化合物能有效抑制 HIV-1 IN 的活性。因此，在本研究中，我们研究了新型二羟基苯基噻吩嘧啶酮衍生物对 LEDGF/p75 依赖性 IN 的抑制活性。我们的研究结果表明，苯基上羟基的位置与这些化合物的 IN 抑制活性密切相关。由于儿茶酚可能与细胞毒性有关，我们还研究了用其他芳香族支架取代儿茶酚的方法。结果，具有更强 IN 抑制活性的 21-23、25 和 26 号化合物提供了很好的候选先导化合物，其中 25 号化合物对 IN 的选择性最强。最后，紫外光谱测定实验表明，噻吩基亚胺基酮类化合物具有似是而非的异构作用模式，因为它们都没有表现出 IN 链转移抑制剂（INSTIs）所特有的 Mg2+ 螯合特性。
• [EN] THIOPHENE-BASED COMPOUNDS EXHIBITING ATP-UTILIZING ENZYME INHIBITORY ACTIVITY, AND COMPOSITIONS, AND USES THEREOF<br/>[FR] COMPOSES A BASE DE THIOPHENE PRESENTANT UNE ACTIVITE D'INHIBITION D'ENZYMES UTILISANT L'ATP, COMPOSITIONS CONTENANT CES COMPOSES ET UTILISATIONS
  申请人：AMPHORA DISCOVERY CORP

  公开号：WO2005033102A2

  公开（公告）日：2005-04-14

  Thiophene-based compounds of formula (I) exhibiting ATP-utilizing enzyme inhibitory activity, methods of using compounds exhibiting ATP-utilizing enzyme inhibitory activity, and compositions comprising compounds exhibiting ATP-utilizing enzyme inhibitory activity, are disclosed. These compounds are useful in the treatment of Alzheimer’s disease, stroke, diabetes, obesity, inflammation and cancer.
• Discovery, structure-activity relationship study and biological evaluation of 2-thioureidothiophene-3-carboxylates as a novel class of C-X-C chemokine receptor 2 (CXCR2) antagonists
  作者：Ding Xue、Wenmin Chen、Nouri Neamati

  DOI：10.1016/j.ejmech.2020.112387

  日期：2020.10

  The C-X-C motif ligand 8 and C-X-C chemokine receptor 2 (CXCL8-CXCR2) axis is involved in pathogenesis of various diseases including inflammation and cancers. Various CXCR2 antagonists are under development for several diseases. Our previous high-throughput cell-based assay specific for CXCR2 has identified a pyrimidine-based compound CX797 acting on CXCR2 down-stream signaling. A lead optimization campaign through scaffold-hopping strategy led to a series of 2-thioureidothiophene-3-carboxylates (TUTP) as novel CXCR2 antagonists. Structure-activity relationship study of TUTPs led to the identification of compound 52 that significantly inhibited CXCR2-mediated beta-arrestin recruitment signaling (IC50 = 1.1 +/- 0.01 mu M) with negligible effect on CXCL8-mediated cAMP signaling and calcium flux. Similar to the known CXCR2 antagonist SB265610, compound 52 inhibited CXCL8-CXCR2 induced phosphorylation of ERK1/2. TUTP compounds also inhibited CXCL8-mediated cell migration and showed synergy with doxorubicin in ovarian cancer cells, thereby supporting TUTPs as promising compounds for cancer treatment. (C) 2020 Elsevier Masson SAS. All rights reserved.
• Identification of PDE4B Over 4D subtype-selective inhibitors revealing an unprecedented binding mode
  作者：Michael Kranz、Michael Wall、Brian Evans、Afjal Miah、Stuart Ballantine、Chris Delves、Brian Dombroski、Jeffrey Gross、Jessica Schneck、James P. Villa、Margarete Neu、Don O. Somers

  DOI：10.1016/j.bmc.2009.03.061

  日期：2009.7

  A PDE4B over 4D-selective inhibitor programme was initiated to capitalise on the recently discovered predominance of the PDE4B subtype in inflammatory cell regulation. The SAR of a tetrahydrobenzothiophene (THBT) series did not agree with either of two proposed docking modes in the 4B binding site. A subsequent X-ray co- crystal structure determination revealed that the THBT ligand displaces the Gln-443 residue, invariably ligand-anchoring in previous PDE4 co-crystal structures, and even shifts helix-15 by 1-2 angstrom. For the first time, several residues of the C-terminus previously proposed to be involved in subtype selectivity are resolved and three of them extend into the ligand binding site potentially allowing for selective drug design. (C) 2009 Elsevier Ltd. All rights reserved.