3-(1H-benzo[d]imidazol-6-yl)-5-(4-fluorophenyl)-1,2,4-oxadiazole

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 3-(1H-benzo[d]imidazol-6-yl)-5-(4-fluorophenyl)-1,2,4-oxadiazole
• 英文别名: 3-(3H-benzimidazol-5-yl)-5-(4-fluorophenyl)-1,2,4-oxadiazole
• 化学式: C₁₅H₉FN₄O
• 分子量: 280.261
• InChiKey: LBOBFSYTLJJUGA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  21
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  67.6
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  3,4-二氨基苯甲腈 在 盐酸 、 盐酸羟胺 、 potassium carbonate 、 N,N'-羰基二咪唑 作用下， 以 乙醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 25.0h， 生成 3-(1H-benzo[d]imidazol-6-yl)-5-(4-fluorophenyl)-1,2,4-oxadiazole
  参考文献：
  名称：

  3-(1H-Benzo[d]imidazol-6-yl)-5-(4-fluorophenyl)-1,2,4-oxadiazole (DDO7232), a Novel Potent Nrf2/ARE Inducer, Ameliorates DSS-Induced Murine Colitis and Protects NCM460 Cells against Oxidative Stress via ERK1/2 Phosphorylation

  摘要：

  溃疡性结肠炎（UC）是一种常见的炎症性肠道疾病，可能破坏结肠的完整性并增加患结直肠癌的风险。氧化应激是UC的关键病因之一，进一步损害整个受影响的结肠。Nrf2-ARE信号通路在对抗氧化和电泳应激方面发挥重要作用。Nrf2-ARE途径的激活为治疗UC提供了不可或缺的防御机制。在这项研究中，我们鉴定了一种新型有效的Nrf2激活剂DDO7232，它对NCM460细胞具有保护作用，并对DSS诱导的小鼠结肠炎具有治疗效果。机制研究表明，DDO7232的Nrf2-ARE诱导活性基于ERK1/2磷酸化的激活。 p-ERK磷酸化Nrf2 Ser40触发了Nrf2进入细胞核并驱动Nrf2依赖的抗氧化蛋白的表达。这些结果不仅揭示了DDO7232的抗氧化机制，还为治疗UC提供了有效的治疗选择。

  DOI：

  10.1155/2018/3271617

文献信息

• Structure-activity and structure-property relationships of novel Nrf2 activators with a 1,2,4-oxadiazole core and their therapeutic effects on acetaminophen (APAP)-induced acute liver injury
  作者：Li-Li Xu、Yu-Feng Wu、Lei Wang、Cui-Cui Li、Li Li、Bin Di、Qi-Dong You、Zheng-Yu Jiang

  DOI：10.1016/j.ejmech.2018.08.071

  日期：2018.9

  The antioxidant function induced by Nrf2 protects the liver from damage. We found a novel Nrf2 activator named compound 25 via structural modification of compound 1 we previously reported. In vitro, compound 25 induced Nrf2 transport into the nucleus and protected hepatocyte L02 cells from APAP-induced cytotoxicity via activating the Nrf2-ARE signaling pathway. In vivo, 25 exhibited therapeutic effects

  Nrf2诱导的抗氧化功能可保护肝脏免受损害。我们通过先前报道的化合物1的结构修饰发现了一种名为化合物25的新型Nrf2活化剂。在体外，化合物25通过激活Nrf2-ARE信号通路，诱导Nrf2转运到细胞核中，并保护肝细胞L02细胞免受APAP诱导的细胞毒性作用。在体内，通过上调Nrf2依赖性抗氧化酶和下调血清中的肝损伤标记物，在对乙酰氨基酚（APAP）诱发的急性肝损伤的小鼠模型中，有25种药物具有治疗作用。在一起，这些结果表明25是有效的Nrf2 / ARE激活剂体外和体内。化合物25的类药物特性进一步揭示了其作为治疗急性肝损伤的治疗药物的潜力。
• Discovery and Modification of in Vivo Active Nrf2 Activators with 1,2,4-Oxadiazole Core: Hits Identification and Structure–Activity Relationship Study
  作者：Li-Li Xu、Jun-Feng Zhu、Xiao-Li Xu、Jie Zhu、Li Li、Mei-Yang Xi、Zheng-Yu Jiang、Ming-Ye Zhang、Fang Liu、Meng-chen Lu、Qi-Chao Bao、Qi Li、Chao Zhang、Jin-Lian Wei、Xiao-Jin Zhang、Lian-Shan Zhang、Qi-Dong You、Hao-Peng Sun

  DOI：10.1021/acs.jmedchem.5b00170

  日期：2015.7.23

  Induction of phase II antioxidant enzymes by activation of Nrf2/ARE pathway has been recognized as a promising strategy for the regulation of oxidative stress-related diseases. Herein we report our effort on the discovery and optimization of Nrf2 activators with 1,2,4-oxadiazole core. Screening of an in-house collection containing 7500 compounds by ARE-luciferase reporter assay revealed a moderate Nrf2 activator, 1. Aimed at obtaining more derivatives efficiently, molecular similarity search by the combination of 2D fingerprint-based and 3D shape-based search was applied to virtually screening the Chemdiv collection. Three derivatives with the same core were identified to have better inductivity of Nrf2 than 1 The best hit 4 was selected as starting point for structurally optimization, leading to a much more potent derivative 32. It in vitro upregulated gene and protein level of Nrf2 as well as its downstream markers such as NQO1, GCLM, and HO-1. It remarkably suppressed inflammation in the in vivo LPS-challenged mouse model. Our results provide a new chemotype as Nrf2-ARE activators which deserve further optimization with the aim to obtain active anti-inflammatory agents through Nrf2-ARE pathway.
• A Comparative Assessment Study of Known Small-Molecule Keap1−Nrf2 Protein–Protein Interaction Inhibitors: Chemical Synthesis, Binding Properties, and Cellular Activity
  作者：Kim T. Tran、Jakob S. Pallesen、Sara M. Ø. Solbak、Dilip Narayanan、Amina Baig、Jie Zang、Alejandro Aguayo-Orozco、Rosa M. C. Carmona、Anthony D. Garcia、Anders Bach

  DOI：10.1021/acs.jmedchem.9b00723

  日期：2019.9.12

  Inhibiting the protein-protein interaction (PPI) between the transcription factor Nrf2 and its repressor protein Keap1 has emerged as a promising strategy to target oxidative stress in diseases, including central nervous system (CNS) disorders. Numerous non-covalent small-molecule Keap1-Nrf2 PPI inhibitors have been reported to date, but many feature suboptimal physicochemical properties for permeating the blood brain barrier, while others contain problematic structural moieties. Here, we present the first side-by-side assessment of all reported Keap1-Nrf2 PPI inhibitor classes using fluorescence polarization, thermal shift assay, and surface plasmon resonance-and further evaluate the compounds in an NQO1 induction cell assay and in counter tests for nonspecific activities. Surprisingly, half of the compounds were inactive or deviated substantially from reported activities, while we confirm the cross-assay activities for others. Through this study, we have identified the most promising Keap1-Nrf2 inhibitors that can serve as pharmacological probes or starting points for developing CNS-active Keap1 inhibitors.