5-chloro-2-hydroxy-N-(4-(trifluoromethoxy)phenyl)benzamide | 634186-00-8

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 5-chloro-2-hydroxy-N-(4-(trifluoromethoxy)phenyl)benzamide
• 英文别名: 5-chloro-2-hydroxy-N-[4-(trifluoromethoxy)phenyl]benzamide
• CAS: 634186-00-8
• 化学式: C₁₄H₉ClF₃NO₃
• 分子量: 331.679
• InChiKey: BATCXRWGXYNAML-UHFFFAOYSA-N

物化性质

• 沸点：
  342.8±42.0 °C(Predicted)
• 密度：
  1.513±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5.1
• 重原子数：
  22
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.07
• 拓扑面积：
  58.6
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  5-chloro-2-hydroxy-N-(4-(trifluoromethoxy)phenyl)benzamide 在 盐酸 作用下， 以 甲醇 、 乙醇 、 水 为溶剂， 反应 24.0h， 生成 5-chloro-2-hydroxy-3-((4-methylpiperazin-1-yl)methyl)-N-(4-(trifluoromethoxy)phenyl)benzamide dihydrochloride
  参考文献：
  名称：

  发现Ascminib（ABL001），BCR-ABL1酪氨酸激酶活性的变构抑制剂

  摘要：

  慢性粒细胞性白血病（CML）源自BCR-ABL1癌蛋白的组成型活性。靶向ATP结合位点的酪氨酸激酶抑制剂（TKIs）已将CML转化为慢性可控制的疾病。但是，由于ATP位点突变阻碍了药物结合，一些患者出现了耐药性。我们描述了asciminib（ABL001）的发现，这是第一种到达临床的变构BCR-ABL1抑制剂。Asciminib结合BCR-ABL1的肉豆蔻口袋，并保持抗TKI耐药性ATP站点突变的活性。尽管由于肉豆蔻酸位点突变会产生抗药性，但这些突变对ATP竞争性抑制剂敏感，因此，asciminib与ATP竞争性TKI的组合可抑制抗药性的出现。使用NMR和X射线的基于片段的筛选产生了肉豆蔻口袋的配体。基于NMR的构象分析指导了这些非活性配体向ABL1抑制剂的转化。对效力，理化，药代动力学和类药物特性进行进一步的基于结构的优化，最终达到了asciminib的要求，目前正在对CML患者进行临床研究。

  DOI：

  10.1021/acs.jmedchem.8b01040
• 作为产物：
  描述：

  5-氯代水杨酸 、 对三氟甲氧基苯胺 在 三氯化磷 作用下， 以 氯苯 为溶剂， 反应 3.0h， 以47%的产率得到5-chloro-2-hydroxy-N-(4-(trifluoromethoxy)phenyl)benzamide
  参考文献：
  名称：

  发现Ascminib（ABL001），BCR-ABL1酪氨酸激酶活性的变构抑制剂

  摘要：

  慢性粒细胞性白血病（CML）源自BCR-ABL1癌蛋白的组成型活性。靶向ATP结合位点的酪氨酸激酶抑制剂（TKIs）已将CML转化为慢性可控制的疾病。但是，由于ATP位点突变阻碍了药物结合，一些患者出现了耐药性。我们描述了asciminib（ABL001）的发现，这是第一种到达临床的变构BCR-ABL1抑制剂。Asciminib结合BCR-ABL1的肉豆蔻口袋，并保持抗TKI耐药性ATP站点突变的活性。尽管由于肉豆蔻酸位点突变会产生抗药性，但这些突变对ATP竞争性抑制剂敏感，因此，asciminib与ATP竞争性TKI的组合可抑制抗药性的出现。使用NMR和X射线的基于片段的筛选产生了肉豆蔻口袋的配体。基于NMR的构象分析指导了这些非活性配体向ABL1抑制剂的转化。对效力，理化，药代动力学和类药物特性进行进一步的基于结构的优化，最终达到了asciminib的要求，目前正在对CML患者进行临床研究。

  DOI：

  10.1021/acs.jmedchem.8b01040

文献信息

• Synthesis, cytotoxicity, and pharmacokinetic evaluations of niclosamide analogs for anti-SARS-CoV-2
  作者：Rui Li、Zherui Zhang、Shuhong Huang、Ke Peng、Hualiang Jiang、Jingshan Shen、Bo Zhang、Xiangrui Jiang

  DOI：10.1016/j.ejmech.2023.115320

  日期：2023.5

  synthesized. The pharmacokinetics of 24 indicates its potential for further research (AUClast was 3-fold of compound 21). Western blot assay indicated that compound 21 could down-regulate SKP2 expression and increase BECN1 levels in Vero-E6 cells, indicating the antiviral mechanism of 21 was related to modulating the autophagy processes in host cells.

  氯硝柳胺是一种口服驱虫药，可通过自噬诱导抑制 SARS-CoV-2 病毒复制，但高细胞毒性和口服生物利用度差限制了其应用。设计并合成了 23 种氯硝柳胺类似物，其中化合物21被发现具有最佳的抗 SARS-CoV-2 功效（EC 50  = 1.00 μM，持续 24 小时），细胞毒性较低（CC 50  = 4.73 μM，持续 48 小时），更好的药代动力学，并且在小鼠的亚急性毒性研究中也具有良好的耐受性。为了进一步改善21的药代动力学，已经合成了三种前药。24的药代动力学表明其具有进一步研究的潜力（AUC最后是化合物的 3 倍21)。Western blot实验表明，化合物21可以下调Vero-E6细胞中SKP2的表达并增加BECN1的水平，表明21的抗病毒机制与调节宿主细胞的自噬过程有关。
• [EN] AMIDE COMPOUND, AND PREPARATION METHOD THEREFOR AND PHARMACEUTICAL USE THEREOF<br/>[FR] COMPOSÉ AMIDE, SON PROCÉDÉ DE PRÉPARATION ET SON UTILISATION PHARMACEUTIQUE<br/>[ZH] 一种酰胺类化合物、其制备方法和制药用途
  申请人：[en]SHANGHAI INSTITUTE OF MATERIA MEDICA, CHINESE ACADEMY OF SCIENCES;[zh]中国科学院上海药物研究所

  公开号：WO2022268145A1

  公开（公告）日：2022-12-29

  本公开涉及一种通式I所表示的酰胺类化合物、其前药、药学上可接受的盐、络合物或溶剂合物。本公开的化合物结构新颖，具有显著的抗病毒活性和抗炎症性活性。
• &lt;p&gt;Reversible Small Molecule Inhibitors of MAO A and MAO B with Anilide Motifs&lt;/p&gt;
  作者：Jens Hagenow、Stefanie Hagenow、Kathrin Grau、Mohammad Khanfar、Lena Hefke、Ewgenij Proschak、Holger Stark

  DOI：10.2147/dddt.s236586

  日期：——

  Background: Ligands consisting of two aryl moieties connected via a short spacer were shown to be potent inhibitors of monoamine oxidases (MAO) A and B, which are known as suitable targets in treatment of neurological diseases. Based on this general blueprint, we synthesized a series of 66 small aromatic amide derivatives as novel MAO A/B inhibitors.Methods: The compounds were synthesized, purified and structurally confirmed by spectroscopic methods. Fluorimetric enzymological assays were performed to determine MAO A/B inhibition properties. Mode and reversibility of inhibition was determined for the most potent MAO B inhibitor. Docking poses and pharmacophore models were generated to confirm the in vitro results.Results: N-(2,4-Dinitrophenyl)benzo [d] [1,3]dioxole-5-carboxamide (55, ST-2043) was found to be a reversible competitive moderately selective MAO B inhibitor (IC50 = 56 nM, K-i = 6.3 nM), while N-(2,4-dinitrophenyl)benzamide (7, ST-2023) showed higher preference for MAO A (IC50 = 126 nM). Computational analysis confirmed in vitro binding properties, where the anilides examined possessed high surface complementarity to MAO A/B active sites.Conclusion: The small molecule anilides with different substitution patterns were identified as potent MAO A/B inhibitors, which were active in nanomolar concentrations ranges. These small and easily accessible molecules are promising motifs, especially for newly designed multitargeted ligands taking advantage of these fragments.
• Structure–activity relationships of antitubercular salicylanilides consistent with disruption of the proton gradient via proton shuttling
  作者：Ill-Young Lee、Todd D. Gruber、Amanda Samuels、Minhan Yun、Bora Nam、Minseo Kang、Kathryn Crowley、Benjamin Winterroth、Helena I. Boshoff、Clifton E. Barry

  DOI：10.1016/j.bmc.2012.10.056

  日期：2013.1

  A series of salicylanilides was synthesized based on a high-throughput screening hit against Mycobacterium tuberculosis. A free phenolic hydroxyl on the salicylic acid moeity is required for activity, and the structure-activity relationship of the aniline ring is largely driven by the presence of electron withdrawing groups. We synthesized 94 analogs exploring substitutions of both rings and the linker region in this series and we have identified multiple compounds with low micromolar potency. Unfortunately, cytotoxicity in a murine macrophage cell line trends with antimicrobial activity, suggesting a similar mechanism of action. We propose that salicylanilides function as proton shuttles that kill cells by destroying the cellular proton gradient, limiting their utility as potential therapeutics. Published by Elsevier Ltd.