(S)-N-(2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)-4,5-dibromo-1H-pyrrole-2-carboxamide

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (S)-N-(2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)-4,5-dibromo-1H-pyrrole-2-carboxamide
• 英文别名: N-[(6S)-2-amino-4,5,6,7-tetrahydro-1,3-benzothiazol-6-yl]-4,5-dibromo-1H-pyrrole-2-carboxamide
• 化学式: C₁₂H₁₂Br₂N₄OS
• 分子量: 420.127
• InChiKey: JLONQDUHUFTMRG-YFKPBYRVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  20
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.33
• 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：

  (S)-N-(2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)-4,5-dibromo-1H-pyrrole-2-carboxamide 在 N-甲基吗啉 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 乙酰氯 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 0.66h， 生成 (S)-N-(2-(2-(5-(benzyloxy)-4-oxo-4H-pyran-2-carboxamido)acetamido)-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)-4,5-dibromo-1H-pyrrole-2-carboxamide
  参考文献：
  名称：

  新型DNA促旋酶抑制剂及其铁载体模拟缀合物的设计，合成和生物学评估。

  摘要：

  细菌DNA促旋酶是开发新型抗菌药物的重要目标，由于全球范围内对抗生素的高度耐药，迫切需要这种细菌。我们设计并合成了新的基于4,5,6,7-四氢苯并[d]噻唑的DNA促旋酶B抑制剂及其与铁载体模拟物的结合物，它们被引入以增加抑制剂对细菌细胞质的吸收。最有效的结合物34对大肠杆菌DNA促旋酶的IC50为58 nM，对大肠杆菌ΔtolC菌株的MIC为14 µg / mL。对于DNA促旋酶抑制剂-铁载体模拟缀合物，在低铁条件下对野生型大肠杆菌的抗菌活性仅获得了较小的改善。

  DOI：

  10.1016/j.bioorg.2019.103550
• 作为产物：
  描述：

  2-溴-4-乙酰氨基环己酮 在 L-酒石酸 、 氢溴酸 、 sodium carbonate 作用下， 以 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 5.75h， 生成 (S)-N-(2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)-4,5-dibromo-1H-pyrrole-2-carboxamide
  参考文献：
  名称：

  Discovery of 4,5,6,7-Tetrahydrobenzo[1,2-d]thiazoles as Novel DNA Gyrase Inhibitors Targeting the ATP-Binding Site

  摘要：

  Bacterial DNA gyrase and topoisomerase IV are essential enzymes that control the topological state of DNA during replication and validated antibacterial drug targets. Starting from a library of marine alkaloid oroidin analogues, we identified low micromolar inhibitors of Escherichia coil DNA gyrase based on the 5,6,7,8-tetrahydroquinazoline and 4,5,6,7-tetrahydrobenzo [1,2-d]thiazole scaffolds. Structure-based optimization of the initial hits resulted in low nanomolar E. coil DNA gyrase inhibitors, some of which exhibited micromolar inhibition of E. coil topoisomerase IV and of Staphylococcus aureus homologues. Some of the compounds possessed modest antibacterial activity against Gram positive bacterial strains, while their evaluation against wild-type, impA and Delta tolC E. coil strains suggests that they are efflux pump substrates and/or do not possess the physicochemical properties necessary for cell wall penetration. Our study provides a rationale for optimization of this class of compounds toward balanced dual DNA gyrase and topoisomerase IV inhibitors with antibacterial activity.

  DOI：

  10.1021/acs.jmedchem.5b00489

文献信息

• Inhibition of Hepatitis C Replication by Targeting the Molecular Chaperone Hsp90: Synthesis and Biological Evaluation of 4,5,6,7‐Tetrahydrobenzo[1,2‐ <i>d</i> ]thiazole Derivatives
  作者：Katja‐Emilia Lillsunde、Tihomir Tomašič、Philipp Schult、Volker Lohmann、Danijel Kikelj、Päivi Tammela

  DOI：10.1002/cmdc.201800724

  日期：2019.2.5

  Cellular chaperones that belong to the heat-shock protein 90 (Hsp90) family are a prerequisite for successful viral propagation for most viruses. The hepatitis C virus (HCV) uses Hsp90 for maturation, folding, and modification of viral proteins. Based on our previous discovery that marine alkaloid analogues with a 4,5,6,7-tetrahydrobenzo[1,2-d]thiazole-2-amine structure show inhibition of HCV replication

  属于热休克蛋白90（Hsp90）家族的细胞伴侣是大多数病毒成功进行病毒繁殖的前提。丙型肝炎病毒（HCV）使用Hsp90来使病毒蛋白成熟，折叠和修饰。基于我们先前的发现，具有4,5,6,7-四氢苯并[1,2-d]噻唑-2-胺结构的海洋生物碱类似物显示出对HCV复制的抑制和与Hsp90的结合，Hsp90是一系列基于12种新化合物的在这个脚手架上进行了设计和合成。目的是改善Hsp90亲和力和抗HCV活性。通过结构优化，对于属于新合成系列的三种化合物，在基因型1b和2a复制子模型中改善了对Hsp90的结合并实现了特定的HCV抑制。此外，
• Novel state-dependent voltage-gated sodium channel modulators, based on marine alkaloids from Agelas sponges
  作者：Žiga Hodnik、Tihomir Tomašić、Lucija Peterlin Mašič、Fiona Chan、Robert W. Kirby、David J. Madge、Danijel Kikelj

  DOI：10.1016/j.ejmech.2013.07.034

  日期：2013.12

  a voltage-gated sodium channel modulator. Here we describe the design and synthesis of conformationally restricted clathrodin analogues incorporating the 4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine moiety and evaluation of their modulatory activities on human voltage-gated sodium channel isoforms Nav1.3, Nav1.4 and Nav1.7, as well as their selectivity against cardiac isoform Nav1.5. Compounds were shown

  Clathrodin是从Agelas海绵中分离的生物碱，在1995年被报道为电压门控钠通道调节剂。在这里，我们描述了结合4,5,6,7-四氢苯并[ d ]噻唑-2-胺基团的构象受限克拉德林类似物的设计和合成，以及它们对人电压门控钠通道亚型Na v 1.3的调节活性的评估， Na v 1.4和Na v 1.7以及它们对心脏亚型Na v 1.5的选择性。已显示化合物具有IC 50的Na v 1.3，Na v 1.4和Na v 1.7的状态依赖性调节剂对于通道的打开灭活状态，在较低的微摩尔范围内的值。初步的结构-活性关系研究表明，疏水相互作用对于结合所有三种测试的同工型非常重要。具有针对Na v 1.4的IC 50值为8μM的化合物4e代表了一种新型的选择性依赖于状态的Na v 1.4通道调节剂。
• 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.
• Design, synthesis and biological evaluation of novel DNA gyrase inhibitors and their siderophore mimic conjugates
  作者：Andraž Lamut、Cristina D. Cruz、Žiga Skok、Michaela Barančoková、Nace Zidar、Anamarija Zega、Lucija Peterlin Mašič、Janez Ilaš、Päivi Tammela、Danijel Kikelj、Tihomir Tomašič

  DOI：10.1016/j.bioorg.2019.103550

  日期：2020.1

  needed because of high level of antibiotic resistance worldwide. We designed and synthesized new 4,5,6,7-tetrahydrobenzo[d]thiazole-based DNA gyrase B inhibitors and their conjugates with siderophore mimics, which were introduced to increase the uptake of inhibitors into the bacterial cytoplasm. The most potent conjugate 34 had an IC50 of 58 nM against Escherichia coli DNA gyrase and displayed MIC of

  细菌DNA促旋酶是开发新型抗菌药物的重要目标，由于全球范围内对抗生素的高度耐药，迫切需要这种细菌。我们设计并合成了新的基于4,5,6,7-四氢苯并[d]噻唑的DNA促旋酶B抑制剂及其与铁载体模拟物的结合物，它们被引入以增加抑制剂对细菌细胞质的吸收。最有效的结合物34对大肠杆菌DNA促旋酶的IC50为58 nM，对大肠杆菌ΔtolC菌株的MIC为14 µg / mL。对于DNA促旋酶抑制剂-铁载体模拟缀合物，在低铁条件下对野生型大肠杆菌的抗菌活性仅获得了较小的改善。
• Discovery of 4,5,6,7-Tetrahydrobenzo[1,2-<i>d</i>]thiazoles as Novel DNA Gyrase Inhibitors Targeting the ATP-Binding Site
  作者：Tihomir Tomašič、Sotirios Katsamakas、Žiga Hodnik、Janez Ilaš、Matjaž Brvar、Tom Solmajer、Sofia Montalvão、Päivi Tammela、Mihailo Banjanac、Gabrijela Ergović、Marko Anderluh、Lucija Peterlin Mašič、Danijel Kikelj

  DOI：10.1021/acs.jmedchem.5b00489

  日期：2015.7.23

  Bacterial DNA gyrase and topoisomerase IV are essential enzymes that control the topological state of DNA during replication and validated antibacterial drug targets. Starting from a library of marine alkaloid oroidin analogues, we identified low micromolar inhibitors of Escherichia coil DNA gyrase based on the 5,6,7,8-tetrahydroquinazoline and 4,5,6,7-tetrahydrobenzo [1,2-d]thiazole scaffolds. Structure-based optimization of the initial hits resulted in low nanomolar E. coil DNA gyrase inhibitors, some of which exhibited micromolar inhibition of E. coil topoisomerase IV and of Staphylococcus aureus homologues. Some of the compounds possessed modest antibacterial activity against Gram positive bacterial strains, while their evaluation against wild-type, impA and Delta tolC E. coil strains suggests that they are efflux pump substrates and/or do not possess the physicochemical properties necessary for cell wall penetration. Our study provides a rationale for optimization of this class of compounds toward balanced dual DNA gyrase and topoisomerase IV inhibitors with antibacterial activity.