5-氯-N-(3,5-二氟苯基)-2-羟基苯甲酰胺 | 634185-46-9

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: 5-氯-N-(3,5-二氟苯基)-2-羟基苯甲酰胺
• 英文名称: N-(3,5-difluorophenyl)-5-chloro-2-hydroxybenzamide
• 英文别名: 5-Chloro-N-(3,5-difluorophenyl)-2-hydroxybenzamide
• CAS: 634185-46-9
• 化学式: C₁₃H₈ClF₂NO₂
• 分子量: 283.662
• InChiKey: FRVRBHNCPAKNHJ-UHFFFAOYSA-N

物化性质

• 沸点：
  320.0±42.0 °C(Predicted)
• 密度：
  1.516±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  19
• 可旋转键数：
  2
• 环数：
  2.0
• 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：
  4

反应信息

• 作为产物：
  描述：

  5-氯代水杨酸 、 2,4-二氟苯胺 在 三氯化磷 作用下， 以 5,5-dimethyl-1,3-cyclohexadiene 为溶剂， 反应 1.5h， 生成 5-氯-N-(3,5-二氟苯基)-2-羟基苯甲酰胺
  参考文献：
  名称：

  Salicylanilide Inhibitors of Toxoplasma gondii

  摘要：

  Toxoplasma gondii (T. gondii) is an apicomplexan parasite that can cause eye disease, brain disease, and death, especially in congenitally infected and immune-compromised people. Novel medicines effective against both active and latent forms of the parasite are greatly needed. The current study focused on the discovery of such medicines by exploring a family of potential inhibitors whose antiapicomplexan activity has not been previously reported. Initial screening efforts revealed that niclosamide, a drug approved for anthelmintic use, possessed promising activity in vitro against T. gondii. This observation inspired the evaluation of the activity of a series of salicylanilides and derivatives. Several inhibitors with activities in the nanomolar range with no appreciable in vitro toxicity to human cells were identified. An initial structure activity relationship was explored. Four compounds were selected for evaluation in an in vivo model of infection, and two derivatives with potentially enhanced pharmacological parameters demonstrated the best activity profiles.

  DOI：

  10.1021/jm3007596

文献信息

• Structure–Function Studies on IMD‐0354 Identifies Highly Active Colistin Adjuvants
  作者：Ansley M. Nemeth、Akash K. Basak、Alexander W. Weig、Santiana A. Marrujo、William T. Barker、Leigh A. Jania、Tyler A. Hendricks、Ashley E. Sullivan、Patrick M. O'Connor、Roberta J. Melander、Beverly H. Koller、Christian Melander

  DOI：10.1002/cmdc.201900560

  日期：2020.1.17

  disclosed that the known IKK-β inhibitor IMD-0354 potently suppresses colistin resistance in several Gram-negative strains. In this study, we explore the structure-activity relationship (SAR) between the IMD-0354 scaffold and colistin resistance suppression, and identify several compounds with more potent activity than the parent against highly colistin-resistant strains of Acinetobacter baumannii and Klebsiella

  由多重耐药（MDR）细菌，特别是革兰氏阴性菌引起的感染是一个不断升级的全球健康威胁。临床医生常常被迫使用最后手段抗生素粘菌素。然而，粘菌素耐药性正变得越来越普遍，导致可能出现多重耐药革兰氏阴性菌感染没有治疗选择的情况。开发规避细菌耐药机制的佐剂是开发新抗生素的一种有前途的正交方法。我们最近披露，已知的 IKK-β 抑制剂 IMD-0354 可有效抑制几种革兰氏阴性菌株的粘菌素耐药性。在这项研究中，我们探索了 IMD-0354 支架与粘菌素耐药性抑制之间的构效关系 (SAR)，并鉴定了几种比母体对鲍曼不动杆菌和肺炎克雷伯菌高度粘菌素耐药菌株具有更有效活性的化合物。
• 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.
• Discovery and Structure Relationships of Salicylanilide Derivatives as Potent, Non-acidic P2X1 Receptor Antagonists
  作者：Maoqun Tian、Aliaa Abdelrahman、Younis Baqi、Eduardo Fuentes、Djamil Azazna、Claudia Spanier、Sabrina Densborn、Sonja Hinz、Ralf Schmid、Christa E. Müller

  DOI：10.1021/acs.jmedchem.0c00435

  日期：2020.6.11

  Antagonists for the ATP-gated ion channel receptor P2X1 have potential as antithrombotics and for treating hyperactive bladder and inflammation. In this study, salicylanilide derivatives were synthesized based on a screening hit. P2X1 antagonistic potency was assessed in 1321N1 astrocytoma cells stably transfected with the human P2X1 receptor by measuring inhibition of the ATP-induced calcium influx. Structure-activity relationships were analyzed, and selectivity versus other P2X receptor subtypes was assessed. The most potent compounds, N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide (1, IC50 0.0192 mu M) and N-[3,5-bis(trifluoromethyl)phenyl]-4-chloro-2-hydroxybenzamide (14, IC50 0.0231 mu M), displayed >500-fold selectivity versus P2X2 and P2X3, and 10-fold selectivity versus P2X4 and P2X7 receptors, and inhibited collagen-induced platelet aggregation. They behaved as negative allosteric modulators, and molecular modeling studies suggested an extracellular binding site. Besides selective P2X1 antagonists, compounds with ancillary P2X4 and/or P2X7 receptor inhibition were discovered. These compounds represent the first potent, non-acidic, allosteric P2X1 receptor antagonists reported to date.
• Identification and synthesis of low-molecular weight cholecystokinin B receptor (CCKBR) agonists as mediators of long-term synaptic potentiation
  作者：Yanmei Zhang、Yican Wang、Yiping Guo、Jinxi Liao、Zhengchao Tu、Yongzhi Lu、Ke Ding、Micky D. Tortorella、Jufang He

  DOI：10.1007/s00044-019-02292-x

  日期：2019.3

  Recently, He et al. reported that CCKB receptors located in the neocortex of the brain when bound to their bound natural ligand, CCK peptides, enhance memory, bringing up the possibility that agonists targeting the CCKB receptor may act as therapeutic agents in diseases in which memory loss is marked as observed in dementia and Alzheimer's. In this report, we describe the synthesis of novel low-molecular weight benzoamine CCKB receptor agonists. The compounds made in this series were determined to be mostly partial agonists, although some antagonists were identified, as well, capable of triggering calcium release in a cell line that overexpresses the CCKB receptor. Compound 35 demonstrated an EC50 of 0.15 mu M in the cell-based assay, but more importantly, several of the compounds, including 35, demonstrated a physiological effect, inducing long-term potentiation in rat brains comparable to the CCK-8 peptide albeit at much higher concentrations. Based on these findings, benzoamines may be the basis for a new series of CCKB receptor agonists in drug-discovery efforts that seek to develop therapeutics to prevent memory loss.
• Salicylanilide Inhibitors of Toxoplasma gondii
  作者：Alina Fomovska、Richard D. Wood、Ernest Mui、Jitenter P. Dubey、Leandra R. Ferreira、Mark R. Hickman、Patricia J. Lee、Susan E. Leed、Jennifer M. Auschwitz、William J. Welsh、Caroline Sommerville、Stuart Woods、Craig Roberts、Rima McLeod

  DOI：10.1021/jm3007596

  日期：2012.10.11

  Toxoplasma gondii (T. gondii) is an apicomplexan parasite that can cause eye disease, brain disease, and death, especially in congenitally infected and immune-compromised people. Novel medicines effective against both active and latent forms of the parasite are greatly needed. The current study focused on the discovery of such medicines by exploring a family of potential inhibitors whose antiapicomplexan activity has not been previously reported. Initial screening efforts revealed that niclosamide, a drug approved for anthelmintic use, possessed promising activity in vitro against T. gondii. This observation inspired the evaluation of the activity of a series of salicylanilides and derivatives. Several inhibitors with activities in the nanomolar range with no appreciable in vitro toxicity to human cells were identified. An initial structure activity relationship was explored. Four compounds were selected for evaluation in an in vivo model of infection, and two derivatives with potentially enhanced pharmacological parameters demonstrated the best activity profiles.