5-bromo-N-(2-chloro-4-nitrophenyl)-2-hydroxybenzamide | 96198-51-5

• 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-bromo-N-(2-chloro-4-nitrophenyl)-2-hydroxybenzamide
• CAS: 96198-51-5
• 化学式: C₁₃H₈BrClN₂O₄
• 分子量: 371.575
• InChiKey: FUTVAINFFRUWFA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  21
• 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：
  95.2
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  5-bromo-N-(2-chloro-4-nitrophenyl)-2-hydroxybenzamide 、 硫光气 生成 6-bromo-3-(2-chloro-4-nitrophenyl)-2-sulfanylidene-1,3-benzoxazin-4-one
  参考文献：
  名称：

  BINDRA R.; SINGH H.; SHARMA S.; IYER R. N., INDIAN J. PHARM. , 1975, 37, NO 6, 133-136

  摘要：

  DOI：
• 作为产物：
  描述：

  5-bromo-N-(2-chloro-4-nitrophenyl)-2-methoxybenzamide 在 三溴化硼 作用下， 以 二氯甲烷 为溶剂， 反应 1.0h， 生成 5-bromo-N-(2-chloro-4-nitrophenyl)-2-hydroxybenzamide
  参考文献：
  名称：

  新型氯硝柳胺衍生佐剂可提高多粘菌素 B 对 MDR 铜绿假单胞菌 DK2 的功效

  摘要：

  铜绿假单胞菌 (P. aeruginosa) DK2 是一种多重耐药 (MDR) 革兰氏阴性细菌病原体，被观察到对“最后手段”抗生素多粘菌素 B (PB) 有严重耐药性。与佐剂的联合治疗已成为重新激活 MDR 细菌耐药性抗生素的有效策略。在这里，我们筛选了一个获批药物库，发现一种驱虫药物氯硝柳胺 (NIC) 可以增强 PB 对 MDR铜绿假单胞菌DK2 的功效。接下来，设计、合成了一系列新型 NIC 衍生佐剂，并评估了与 PB 的协同活性。其中，15与 PB 的组合显示出对铜绿假单胞菌DK2的优异消除体外和体内与单次给药相比。此外，这种组合减缓了 DK2 的 PB 抗性进展，同时降低了潜在毒性。总体而言，这项研究提供了开发抗生素佐剂以增强 PB 对抗 MDR铜绿假单胞菌感染的策略。

  DOI：

  10.1016/j.ejmech.2022.114318

文献信息

• Application of niclosamide and analogs as small molecule inhibitors of Zika virus and SARS-CoV-2 infection
  作者：Khalida Shamim、Miao Xu、Xin Hu、Emily M Lee、Xiao Lu、Ruili Huang、Pranav Shah、Xin Xu、Catherine Z. Chen、Min Shen、Hui Guo、Lu Chen、Zina Itkin、Richard T. Eastman、Paul Shinn、Carleen Klumpp-Thomas、Sam Michael、Anton Simeonov、Donald C. Lo、Guo-li Ming、Hongjun Song、Hengli Tang、Wei Zheng、Wenwei Huang

  DOI：10.1016/j.bmcl.2021.127906

  日期：2021.5

  focusing on the anilide and salicylic acid regions of niclosamide to improve physicochemical properties such as microsomal metabolic stability, permeability and solubility. We found that the 5-bromo substitution in the salicylic acid region retains potency while providing better drug-like properties. Other modifications in the anilide region with 2′-OMe and 2′-H substitutions were also advantageous

  寨卡病毒已成为全球人类健康的潜在威胁。之前的药物再利用筛选确定已批准的驱虫药氯硝柳胺是寨卡病毒感染的小分子抑制剂。然而，由于抗蠕虫药物通常设计为口服时吸收率较低，氯硝柳胺非常有限的生物利用度可能会阻碍其直接重新用作抗病毒药物。在这里，我们针对氯硝柳胺的苯胺和水杨酸区域进行了 SAR 研究，以改善微粒体代谢稳定性、渗透性和溶解性等理化性质。我们发现水杨酸区域的 5-溴取代保留了效力，同时提供了更好的药物样特性。具有 2'-OMe 和 2'-H 取代的苯胺区域的其他修饰也是有利的。我们发现4'-NO 2取代基可以被4'-CN或4'-CF 3取代基取代。总之，这些修饰为优化氯硝柳胺的结构提供了基础，以改善氯硝柳胺类似物作为治疗寨卡和其他病毒感染的药物先导候选药物的全身暴露。事实上，关键的类似物也能够将细胞从 SARS-CoV-2 感染的细胞病变效应中拯救出来，这表明与针对 COVID-19 大流行的治疗策略的相关性。
• Design, Synthesis, and Evaluation of Niclosamide Analogs as Therapeutic Agents for Enzalutamide-Resistant Prostate Cancer
  作者：Borui Kang、Madhusoodanan Mottamal、Qiu Zhong、Melyssa Bratton、Changde Zhang、Shanchun Guo、Ahamed Hossain、Peng Ma、Qiang Zhang、Guangdi Wang、Florastina Payton-Stewart

  DOI：10.3390/ph16050735

  日期：——

  Niclosamide effectively downregulates androgen receptor variants (AR-Vs) for treating enzalutamide and abiraterone-resistant prostate cancer. However, the poor pharmaceutical properties of niclosamide due to its solubility and metabolic instability have limited its clinical utility as a systemic treatment for cancer. A novel series of niclosamide analogs was prepared to systematically explore the structure–activity relationship and identify active AR-Vs inhibitors with improved pharmaceutical properties based on the backbone chemical structure of niclosamide. Compounds were characterized using 1H NMR, 13C NMR, MS, and elemental analysis. The synthesized compounds were evaluated for antiproliferative activity and downregulation of AR and AR-V7 in two enzalutamide-resistant cell lines, LNCaP95 and 22RV1. Several of the niclosamide analogs exhibited equivalent or improved anti-proliferation effects in LNCaP95 and 22RV1 cell lines (B9, IC50 LNCaP95 and 22RV1 = 0.130 and 0.0997 μM, respectively), potent AR-V7 down-regulating activity, and improved metabolic stability. In addition, both a traditional structure–activity relationship (SAR) and 3D-QSAR analysis were performed to guide further structural optimization. The presence of two -CF3 groups of the most active B9 in the sterically favorable field and the presence of the -CN group of the least active B7 in the sterically unfavorable field seem to make B9 more potent than B7 in the antiproliferative activity.

  尼可刹米能有效下调雄激素受体变体（AR-Vs），用于治疗恩杂鲁胺和阿比特龙耐药的前列腺癌。然而，由于尼可刹米的溶解性和代谢不稳定性，其药物特性较差，限制了其作为全身性癌症治疗药物的临床应用。本研究制备了一系列新型尼可刹米类似物，以系统地探索其结构-活性关系，并在尼可刹米骨架化学结构的基础上鉴定出具有更好药物特性的活性 AR-Vs 抑制剂。利用 1H NMR、13C NMR、MS 和元素分析对化合物进行了表征。对合成的化合物进行了评估，以确定其在两种耐恩扎鲁胺细胞系（LNCaP95 和 22RV1）中的抗增殖活性以及对 AR 和 AR-V7 的下调作用。几种烟酰胺类似物在 LNCaP95 和 22RV1 细胞系中表现出了同等或更好的抗增殖效果（B9，IC50 LNCaP95 和 22RV1 分别为 0.130 和 0.0997 μM）、强效的 AR-V7 下调活性以及更好的代谢稳定性。此外，还进行了传统的结构-活性关系（SAR）和三维-QSAR 分析，以指导进一步的结构优化。活性最高的 B9 的两个 -CF3 基团位于立体有利区域，而活性最低的 B7 的 -CN 基团位于立体不利区域，这似乎使 B9 的抗增殖活性比 B7 更强。
• 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.
• SALICYLANILIDES ENHANCE ORAL DELIVERY OF THERAPEUTIC PEPTIDES
  申请人：Fogelman Alan M.

  公开号：US20090163408A1

  公开（公告）日：2009-06-25

  This invention pertains to the surprising discovery that salicylanilides, e.g., niclosamide and/or niclosamide analogues when orally administered in conjunction with a peptide pharmaceutical (e.g., a class A amphipathic helical peptide as described herein) significantly increases the bioavailability of that peptide. Methods of peptide delivery using such “delivery agents” and pharmaceutical formulations are provided.
• SALICYLANILIDE MODIFIED PEPTIDES FOR USE AS ORAL THERAPEUTICS
  申请人：Fogelman Alan M.

  公开号：US20110183889A1

  公开（公告）日：2011-07-28

  This invention pertains to the surprising discovery that salicylanilides, e.g., niclosamide and/or niclosamide analogues can be reacted with a therapeutically active peptide to produce a modified peptide complex that shows increased resistance to proteolysis and that shows higher bioactivity when orally administered than the unmodified peptide.