N-(3,5-二氯苯基)-2-羟基萘-1-甲酰胺 | 63245-19-2

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 中文名称: N-(3,5-二氯苯基)-2-羟基萘-1-甲酰胺
• 英文名称: N-(3,5-dichlorophenyl)-2-hydroxynaphthalene-1-carboxamide
• 英文别名: N-(3,5-Dichlorophenyl)-2-hydroxy-1-naphthamide
• CAS: 63245-19-2
• 化学式: C₁₇H₁₁Cl₂NO₂
• 分子量: 332.186
• InChiKey: WUYQNFJDXZDYRR-UHFFFAOYSA-N

物化性质

• 沸点：
  436.6±45.0 °C(Predicted)
• 密度：
  1.477±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5.5
• 重原子数：
  22
• 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：
  49.3
• 氢给体数：
  2
• 氢受体数：
  2

反应信息

• 作为产物：
  描述：

  2-羟基-1-萘甲酸 在 三氯化磷 作用下， 以 氯苯 为溶剂， 生成 N-(3,5-二氯苯基)-2-羟基萘-1-甲酰胺
  参考文献：
  名称：

  Searching new structural scaffolds for BRAF inhibitors. An integrative study using theoretical and experimental techniques

  摘要：

  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.

  DOI：

  10.1016/j.bioorg.2019.103125

文献信息

• Hydroxynaphthalenecarboxamides and substituted piperazinylpropandiols, two new series of BRAF inhibitors. A theoretical and experimental study
  作者：Ludmila E. Campos、Francisco Garibotto、Emilio Angelina、Jiri Kos、Tomas Gonec、Pavlina Marvanova、Marcela Vettorazzi、Michal Oravec、Izabela Jendrzejewska、Josef Jampilek、Sergio E. Alvarez、Ricardo D. Enriz

  DOI：10.1016/j.bioorg.2020.104145

  日期：2020.10

  decrease resistance progress. Considering the data from our previous report, here we studied two series of derivatives of structural scaffolds as potential BRAF inhibitors: hydroxynaphthalenecarboxamides and substituted piperazinylpropandiols. Our results indicate that structural analogues of substituted piperazinylpropandiols do not show significantly better activities to that previously reported.

  致癌突变激酶BRAF V600E是有吸引力的分子靶标，因为它在包括黑素瘤在内的多种人类癌症中表达。迄今为止，FDA仅批准了三种BRAF小抑制剂用于治疗转移性黑色素瘤患者：VemuRAfenib，DabRAfenib和EncoRAfenib。尽管在临床试验中已经探究了许多方案治疗方法，但是BRAF抑制作用有限，因为患者总是会产生与治疗相关的耐药性和继发性毒性作用。这些局限性凸显了设计具有不同结构的新型更好抑制剂的重要性，这些抑制剂可以在酶的活性位点建立不同的相互作用，从而降低抗药性。 考虑到我们以前的报告中的数据，在这里我们研究了作为潜在的BRAF抑制剂的结构支架的两个系列衍生物：羟基萘甲酰胺和取代的哌嗪基丙二醇。我们的结果表明，取代的哌嗪基丙二醇的结构类似物没有显示出比以前报道的明显更好的活性。相反，在Lu1205 BRAF V600E中，羟基萘甲酰胺衍生物显着抑制了细胞活力和ERK磷酸化
• INFLAMMATORY CYTOKINE RELEASE INHIBITOR
  申请人：MUTO Susumu

  公开号：US20090192122A2

  公开（公告）日：2009-07-30

  A medicament having inhibitory activity against NF-κB activation, which comprises a compound represented by the following general formula (I) or a pharmacologically acceptable salt as an active ingredient: wherein X represents a connecting group, A represents hydrogen atom or acetyl group, E represents an aryl group or a heteroaryl group, and ring X represents an arene or a heteroarene.

  一种具有抑制NF-κB激活活性的药物，其包括以下通式(I)所表示的化合物或其药理学上可接受的盐作为活性成分：其中X代表连接基，A代表氢原子或乙酰基，E代表芳基或杂芳基，环X代表芳烃或杂芳烃。
• Inhibitors against the production and release of inflammatory cytokines
  申请人：——

  公开号：US20040259877A1

  公开（公告）日：2004-12-23

  A medicament having inhibitory activity against NF-&kgr;B activation, which comprises a compound represented by the following general formula (I) or a pharmacologically acceptable salt as an active ingredient: 1 wherein X represents a connecting group, A represents hydrogen atom or acetyl group, E represents an aryl group or a heteroaryl group, and ring X represents an arene or a heteroarene.

  一种具有抑制NF-&kgr;B激活活性的药物，其包括以下通式（I）所表示的化合物或其药学上可接受的盐作为活性成分：1其中X表示连接基，A表示氢原子或乙酰基，E表示芳基或杂芳基，环X表示芳烃或杂芳烃。
• Inflammatory cytokine release inhibitor
  申请人：Institute of Medicinal Molecular Design, Inc.

  公开号：US08097759B2

  公开（公告）日：2012-01-17

  A medicament having inhibitory activity against NF-κB activation, which comprises a compound represented by the following general formula (I) or a pharmacologically acceptable salt as an active ingredient: wherein X represents a connecting group, A represents hydrogen atom or acetyl group, E represents an aryl group or a heteroaryl group, and ring X represents an arene or a heteroarene.

  一种具有抑制NF-κB活化活性的药物，其包括以下一般公式(I)所代表的化合物或药理学上可接受的盐作为活性成分：其中X代表连接基，A代表氢原子或乙酰基，E代表芳基或杂芳基，环X代表芳烃或杂芳烃。
• INHIBITORS AGAINST THE PRODUCTION AND RELEASE OF INFLAMMATORY CYTOKINES
  申请人：Institute of Medicinal Molecular Design, Inc.

  公开号：EP1352650B1

  公开（公告）日：2012-03-07