N-(6-aminobenzo[d]thiazol-2-yl)-4,5-dibromo-1H-pyrrole-2-carboxamide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并噻唑类
• 英文名称: N-(6-aminobenzo[d]thiazol-2-yl)-4,5-dibromo-1H-pyrrole-2-carboxamide
• 英文别名: N-(6-amino-1,3-benzothiazol-2-yl)-4,5-dibromo-1H-pyrrole-2-carboxamide
• 化学式: C₁₂H₈Br₂N₄OS
• 分子量: 416.096
• InChiKey: ANDKBRLNIKATCM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  20
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  112
• 氢给体数：
  3
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  N-(6-aminobenzo[d]thiazol-2-yl)-4,5-dibromo-1H-pyrrole-2-carboxamide 在 三乙胺 、 sodium hydroxide 作用下， 以 1,4-二氧六环 、 甲醇 为溶剂， 反应 27.0h， 生成 2-((2-(4,5-dibromo-1H-pyrrole-2-carboxamido)benzo[d]thiazol-6-yl)amino)-2-oxoacetic acid
  参考文献：
  名称：

  发现基于苯并噻唑支架的DNA促旋酶B抑制剂

  摘要：

  细菌DNA促旋酶和拓扑异构酶IV控制复制过程中DNA的拓扑状态，并且是抗菌药物发现的有效靶标。从我们最近报道的基于4,5,6,7-四氢苯并[1,2- d ]噻唑的DNA促旋酶B抑制剂开始，我们用苯并噻唑-2,6-二胺支架和在位置2和3互换的取代基取代了它们的中心核6.这导致来自大肠杆菌的DNA回旋酶的等量纳摩尔抑制剂表现出对两种细菌的金黄色葡萄球菌DNA回旋酶和拓扑异构酶IV的改善的抑制。化合物27是来自大肠杆菌和金黄色葡萄球菌的DNA促旋酶和拓扑异构酶IV的最平衡抑制剂。2-（（2-（4,5-dibromo-1 H-吡咯-2-羧酰胺基）苯并噻唑-6-基）氨基）-2-氧乙酸（24）与大肠杆菌DNA的复合物的晶体结构旋转酶B揭示了该抑制剂在ATP结合口袋中的结合模式。只有一些化合物对革兰氏阳性细菌具有弱的抗菌活性。这些结果为针对具有抗菌活性的双重DNA促旋酶和拓扑异构酶IV抑制剂的基于结构的优化提供了基础。

  DOI：

  10.1021/acs.jmedchem.6b00864
• 作为产物：
  描述：

  2-氨基-6-硝基苯并噻唑 在 palladium 10% on activated carbon 、 氢气 、 sodium carbonate 作用下， 以 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 20.0~80.0 ℃ 、150.0 kPa 条件下， 生成 N-(6-aminobenzo[d]thiazol-2-yl)-4,5-dibromo-1H-pyrrole-2-carboxamide
  参考文献：
  名称：

  具有抗菌活性的双重大肠杆菌DNA促旋酶A和B抑制剂。

  摘要：

  耐多药细菌的出现是对全球健康的威胁，因此有必要发现新的抗菌素和与细菌感染作斗争的新策略。我们报告一流的DNA回旋酶B（GyrB）抑制剂/环丙沙星杂种，对大肠杆菌表现出抗菌活性。尽管DNA旋转酶ATPase抑制实验，DNA旋转酶超螺旋测定和体外抗菌测定表明杂合体与大肠杆菌GyrA和GyrB亚基结合，但与GyrA氟喹诺酮结合位点的相互作用似乎是其抗菌活性的唯一原因。我们的研究结果为通过与高渗透性GyrA抑制剂环丙沙星结合促进非渗透性GyrB抑制剂进入细菌的新概念奠定了基础。

  DOI：

  10.1002/cmdc.201900607

文献信息

• From Bacteria to Cancer: A Benzothiazole-Based DNA Gyrase B Inhibitor Redesigned for Hsp90 C-Terminal Inhibition
  作者：Kyler W. Pugh、Zheng Zhang、Jian Wang、Xiuzhi Xu、Vitumbiko Munthali、Ang Zuo、Brian S. J. Blagg

  DOI：10.1021/acsmedchemlett.0c00100

  日期：2020.8.13

  Heat shock protein 90 (Hsp90) is a molecular chaperone that is responsible for the folding and maturation of client proteins that are associated with all ten hallmarks of cancer. Hsp90 N-terminal pan inhibitors have experienced unfavorable results in clinical trials due to induction of the heat shock response (HSR), among other concerns. Novobiocin, a well characterized DNA gyrase B inhibitor, was

  热休克蛋白 90 (Hsp90) 是一种分子伴侣，负责与癌症的所有十个标志相关的客户蛋白的折叠和成熟。由于热休克反应 (HSR) 的诱导以及其他问题，Hsp90 N 端泛抑制剂在临床试验中经历了不利的结果。Novobiocin 是一种充分表征的 DNA 促旋酶 B 抑制剂，被鉴定为第一个 Hsp90 C 末端抑制剂，它在不诱导 HSR 的情况下表现出抗癌作用。在这封信中，设计、合成和评估了一个源自苯并噻唑支架的 Hsp90 C 端抑制剂库，已知可抑制 DNA 促旋酶 B。发现几种化合物通过 Hsp90 C 末端抑制对 MCF-7 和 SKBr3 乳腺癌细胞系表现出低微摩尔活性。
• Discovery of Benzothiazole Scaffold-Based DNA Gyrase B Inhibitors
  作者：Marina Gjorgjieva、Tihomir Tomašič、Michaela Barančokova、Sotirios Katsamakas、Janez Ilaš、Päivi Tammela、Lucija Peterlin Mašič、Danijel Kikelj

  DOI：10.1021/acs.jmedchem.6b00864

  日期：2016.10.13

  resulted in equipotent nanomolar inhibitors of DNA gyrase from Escherichia coli displaying improved inhibition of Staphylococcus aureus DNA gyrase and topoisomerase IV from both bacteria. Compound 27 was the most balanced inhibitor of DNA gyrase and topoisomerase IV from both E. coli and S. aureus. The crystal structure of the 2-((2-(4,5-dibromo-1H-pyrrole-2-carboxamido)benzothiazol-6-yl)amino)-2-oxoacetic

  细菌DNA促旋酶和拓扑异构酶IV控制复制过程中DNA的拓扑状态，并且是抗菌药物发现的有效靶标。从我们最近报道的基于4,5,6,7-四氢苯并[1,2- d ]噻唑的DNA促旋酶B抑制剂开始，我们用苯并噻唑-2,6-二胺支架和在位置2和3互换的取代基取代了它们的中心核6.这导致来自大肠杆菌的DNA回旋酶的等量纳摩尔抑制剂表现出对两种细菌的金黄色葡萄球菌DNA回旋酶和拓扑异构酶IV的改善的抑制。化合物27是来自大肠杆菌和金黄色葡萄球菌的DNA促旋酶和拓扑异构酶IV的最平衡抑制剂。2-（（2-（4,5-dibromo-1 H-吡咯-2-羧酰胺基）苯并噻唑-6-基）氨基）-2-氧乙酸（24）与大肠杆菌DNA的复合物的晶体结构旋转酶B揭示了该抑制剂在ATP结合口袋中的结合模式。只有一些化合物对革兰氏阳性细菌具有弱的抗菌活性。这些结果为针对具有抗菌活性的双重DNA促旋酶和拓扑异构酶IV抑制剂的基于结构的优化提供了基础。
• Searching new structural scaffolds for BRAF inhibitors. An integrative study using theoretical and experimental techniques
  作者：Ludmila E. Campos、Francisco M. Garibotto、Emilio Angelina、Jiri Kos、Tihomir Tomašič、Nace Zidar、Danijel Kikelj、Tomas Gonec、Pavlina Marvanova、Petr Mokry、Josef Jampilek、Sergio E. Alvarez、Ricardo D. Enriz

  DOI：10.1016/j.bioorg.2019.103125

  日期：2019.10

  The identification of the V600E activating mutation in the protein kinase BRAF in around 50% of melanoma patients has driven the development of highly potent small inhibitors (BRAFi) of the mutated protein. To date, Dabrafenib and Vemurafenib, two specific BRAFi, have been clinically approved for the treatment of metastatic melanoma. Unfortunately, after the initial response, tumors become resistant and patients develop a progressive and lethal disease, making imperative the development of new therapeutic options. The main objective of this work was to find new BRAF inhibitors with different structural scaffolds than those of the known inhibitors. Our study was carried out in different stages; in the first step we performed a virtual screening that allowed us to identify potential new inhibitors. In the second step, we synthesized and tested the inhibitory activity of the novel compounds founded. Finally, we conducted a molecular modelling study that allowed us to understand interactions at the molecular level that stabilize the formation of the different molecular complexes.Our theoretical and experimental study allowed the identification of four new structural scaffolds, which could be used as starting structures for the design and development of new inhibitors of BRAF. Our experimental data indicate that the most active compounds reduced significantly ERK1/2 phosphorylation, a measure of BRAF inhibition, and cell viability. Thus, from our theoretical and experimental results, we propose new substituted hydroxynaphthalenecarboxamides, N-(hetero)aryl-piperazinylhydroxyalkylphenylcarbamates, substituted piperazinylethanols and substituted piperazinylpropandiols as initial structures for the development of new inhibitors for BRAF. Moreover, by performing QTAIM analysis, we are able to describe in detail the molecular interactions that stabilize the different Ligand-Receptor complexes. Such analysis indicates which portion of the different molecules must be changed in order to obtain an increase in the binding affinity of these new ligands.
• Dual <i>Escherichia coli</i> DNA Gyrase A and B Inhibitors with Antibacterial Activity
  作者：Benedetta Fois、Žiga Skok、Tihomir Tomašič、Janez Ilaš、Nace Zidar、Anamarija Zega、Lucija Peterlin Mašič、Petra Szili、Gábor Draskovits、Ákos Nyerges、Csaba Pál、Danijel Kikelj

  DOI：10.1002/cmdc.201900607

  日期：2020.2.5

  facilitating entry of nonpermeating GyrB inhibitors into bacteria by conjugation with ciprofloxacin, a highly permeable GyrA inhibitor. A hybrid molecule containing GyrA and GyrB inhibitor parts entering the bacterial cell would then elicit a strong antibacterial effect by inhibition of both the GyrA and GyrB subunits of DNA gyrase and potentially slow bacterial resistance development.

  耐多药细菌的出现是对全球健康的威胁，因此有必要发现新的抗菌素和与细菌感染作斗争的新策略。我们报告一流的DNA回旋酶B（GyrB）抑制剂/环丙沙星杂种，对大肠杆菌表现出抗菌活性。尽管DNA旋转酶ATPase抑制实验，DNA旋转酶超螺旋测定和体外抗菌测定表明杂合体与大肠杆菌GyrA和GyrB亚基结合，但与GyrA氟喹诺酮结合位点的相互作用似乎是其抗菌活性的唯一原因。我们的研究结果为通过与高渗透性GyrA抑制剂环丙沙星结合促进非渗透性GyrB抑制剂进入细菌的新概念奠定了基础。