N-(3,5-bis(trifluoromethyl)phenyl)-5-chloro-2-methoxybenzamide

• 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: N-(3,5-bis(trifluoromethyl)phenyl)-5-chloro-2-methoxybenzamide
• 英文别名: N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-methoxy-benzamide；N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-methoxybenzamide
• 化学式: C₁₆H₁₀ClF₆NO₂
• 分子量: 397.704
• InChiKey: CCGKBWKPPIGCGJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.7
• 重原子数：
  26
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  38.3
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  N-(3,5-bis(trifluoromethyl)phenyl)-5-chloro-2-methoxybenzamide 在 三溴化硼 作用下， 以 二氯甲烷 为溶剂， 以105 mg的产率得到N-[3,5-双(三氟甲基)苯基]-5-氯-2-羟基苯甲酰胺
  参考文献：
  名称：

  Structure–Activity Relationship Studies on Diversified Salicylamide Derivatives as Potent Inhibitors of Human Adenovirus Infection

  摘要：

  The effective treatment of adenovirus (HAdV) infections in immunocompromised patients still poses great challenges. Herein, we reported our continued efforts to optimize a series of salicylamide derivatives as potent inhibitors of HAdV infection. Of these, nine compounds (11, 13, 14, 17, 20, 58, 60, 62, and 70) showed significantly improved anti-HAdV activities with nanomolar to submicromolar IC50 values and high selectivity indexes (SI > 100), indicating better safety windows, compared to those of the lead compound niclosamide. Our mechanistic assays suggest that compounds 13, 62, and 70 exert their activities in the HAdV entry pathway, while compounds 14 and 60 likely target the HAdV DNA replication, and 11, 17, 20, and 58 inhibit later steps after DNA replication. Given the broad anti-viral activity profile of niclosamide, these derivatives may also offer therapeutic potential for other viral infections.

  DOI：

  10.1021/acs.jmedchem.9b01950
• 作为产物：
  描述：

  N-[3,5-双(三氟甲基)苯基]-5-氯-2-羟基苯甲酰胺 在 sodium hydroxide 作用下， 以 DMF (N,N-dimethyl-formamide) 、 乙醇 、 水 为溶剂， 反应 2.02h， 生成 N-(3,5-bis(trifluoromethyl)phenyl)-5-chloro-2-methoxybenzamide
  参考文献：
  名称：

  O-SUBSTITUTED HYDROXYARYL DERIVATIVES

  摘要：

  公开号：

  EP1512397B1

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。
• [EN] COMPOUNDS AND METHODS FOR POTENTIATING COLISTIN ACTIVITY<br/>[FR] COMPOSÉS ET PROCÉDÉS POUR POTENTIALISER L'ACTIVITÉ DE LA COLISTINE
  申请人：UNIV NOTRE DAME DU LAC

  公开号：WO2021086567A1

  公开（公告）日：2021-05-06

  Infections caused by multidrug-resistant (MDR) bacteria, particularly Gram-negative bacteria, are an escalating global health threat. Often clinicians are forced to administer the last resort antibiotic colistin, however colistin resistance is becoming increasingly prevalent, giving rise to the potential for a situation in which there are no treatment options for MDR Gram-negative infections. The development of adjuvants that circumvent bacterial resistance mechanisms is a promising orthogonal approach to the development of new antibiotics. We recently disclosed that the known IKK-β inhibitor IMD-0354 potently suppresses colistin resistance in several Gram-negative strains. In this disclosure, 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 pneumoniae.

  由多药耐药（MDR）细菌引起的感染，特别是革兰氏阴性细菌，是一种不断加剧的全球健康威胁。通常情况下，临床医生被迫使用最后的抗生素科利星，然而科利星耐荐性越来越普遍，导致可能出现无法治疗MDR革兰氏阴性细菌感染的情况。开发能够规避细菌耐药机制的辅助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能够有效抑制几种革兰氏阴性菌株对科利星的耐药性。在这一披露中，我们探讨了IMD-0354骨架与科利星耐药抑制之间的结构活性关系（SAR），并确定了几种比母体更具有强效活性的化合物，对鲍曼不动杆菌和肺炎克雷伯氏菌高度耐科利星的菌株具有更强的活性。
• 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.
• [EN] NOVEL PRODRUG SALTS<br/>[FR] NOUVEAUX SELS DE PROMÉDICAMENT
  申请人：AEROMICS LLC

  公开号：WO2015069961A1

  公开（公告）日：2015-05-14

  Provided are novel prodrug salts of selective aquaporin inhibitors, their use as pharmaceuticals, and pharmaceutical compositions comprising them, and novel processes for their synthesis and novel intermediates for use in their synthesis. Also provided is use of a compound for the prophylaxis, treatment, and control of aquaporin-mediated conditions. Aquaporin inhibitors, e.g., inhibitors of AQP4 and/or AQP2, may be of utility in the treatment or control of diseases of water imbalance, for example edema (particularly edema of the brain and spinal cord), hyponatremia, and excess fluid retention, as well as diseases such as epilepsy, retinal ischemia and other diseases of the eye, myocardial ischemia, myocardial ischemia/reperfusion injury, myocardial infarction, myocardial hypoxia, congestive heart failure, sepsis, and neuromyelitis optica, as well as migraines.