(Z)-N′-hydroxy-1H-benzo[d]imidazole-5-carboximidamide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并咪唑类
• 英文名称: (Z)-N′-hydroxy-1H-benzo[d]imidazole-5-carboximidamide
• 英文别名: N'-hydroxy-3H-benzimidazole-5-carboximidamide
• 化学式: C₈H₈N₄O
• mdl: MFCD13188575
• 分子量: 176.178
• InChiKey: SOHZNRZEBBMFNP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.9
• 重原子数：
  13
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  87.3
• 氢给体数：
  3
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  (Z)-N′-hydroxy-1H-benzo[d]imidazole-5-carboximidamide 在 sodium methylate 、 N,N'-羰基二咪唑 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 3-(1-methyl-1H-benzo[d]imidazol-6-yl)-5-(naphthalen-2-yl)-1,2,4-oxadiazole
  参考文献：
  名称：

  Discovery and Modification of in Vivo Active Nrf2 Activators with 1,2,4-Oxadiazole Core: Hits Identification and Structure–Activity Relationship Study

  摘要：

  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.

  DOI：

  10.1021/acs.jmedchem.5b00170
• 作为产物：
  描述：

  3,4-二氨基苯甲腈 在 盐酸 、 盐酸羟胺 、 potassium carbonate 作用下， 以 乙醇 、 水 为溶剂， 反应 24.0h， 生成 (Z)-N′-hydroxy-1H-benzo[d]imidazole-5-carboximidamide
  参考文献：
  名称：

  具有1,2,4-恶二唑核心的新型Nrf2激活剂的结构-活性和结构-性质关系及其对乙酰氨基酚（APAP）诱导的急性肝损伤的治疗作用

  摘要：

  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。

  DOI：

  10.1016/j.ejmech.2018.08.071

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。
• [EN] OXADIAZOLE FUSED HETEROCYCLIC DERIVATIVES USEFUL FOR THE TREATMENT OF MULTIPLE SCLEROSIS<br/>[FR] DÉRIVÉS HÉTÉROCYCLIQUES FUSIONNÉS D'OXADIAZOLE UTILES POUR LE TRAITEMENT DE LA SCLÉROSE EN PLAQUES
  申请人：MERCK SERONO SA

  公开号：WO2010069949A1

  公开（公告）日：2010-06-24

  The invention provides compounds of Formula (I) for the treatment of multiple sclerosis and other diseases.

  该发明提供了用于治疗多发性硬化症和其他疾病的化合物的公式（I）。
• [EN] TRIAZOLE OXADIAZOLES DERIVATIVES<br/>[FR] DÉRIVÉS DE TRIAZOLES ET D'OXADIAZOLES
  申请人：MERCK SERONO SA

  公开号：WO2009080663A1

  公开（公告）日：2009-07-02

  The invention relates to compounds of formula (I), wherein R1, R2, Ra, Rb, X have the meanings given in claim 1. The compounds are useful e.g. in the treatment of autoimmune disorders, such as multiple sclerosis.

  该发明涉及公式（I）的化合物，其中R1、R2、Ra、Rb、X具有权利要求书中给定的含义。这些化合物可用于治疗自身免疫性疾病，如多发性硬化症。
• 3-(1H-Benzo[<i>d</i>]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
  作者：Li-Li Xu、Tian Liu、Lei Wang、Li Li、Yu-Feng Wu、Cui-Cui Li、Bin Di、Qi-Dong You、Zheng-Yu Jiang

  DOI：10.1155/2018/3271617

  日期：——

  Ulcerative colitis (UC) is a common inflammatory bowel disease that can destroy the integrity of the colon and increase the risk of colorectal cancer. Oxidative stress is one of the critical pathogenic factors for UC, further impairing the entire affected colon. The Nrf2-ARE signaling pathway plays an important role in counteracting oxidative and electrophilic stress. Activation of the Nrf2-ARE pathway provides an indispensable defense mechanism for the treatment of UC. In this study, we identified a novel effective Nrf2 activator, DDO7232, which showed protective effects on NCM460 cells and therapeutic effects on DSS-induced colitis in mice. Mechanistic studies indicated that the Nrf2-ARE-inducing activity of DDO7232 was based on the activation of the ERK1/2 phosphorylation. The phosphorylation of Nrf2 Ser40 by p-ERK triggered the transport of Nrf2 into the nucleus and drove the expression of Nrf2-dependent antioxidant proteins. These results not only revealed the antioxidant mechanisms of DDO7232 but also provided an effective therapeutic option for the treatment of UC.

  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。
• Synthesis of carboxyimidamide-substituted benzo[c][1,2,5]oxadiazoles and their analogs, and evaluation of biological activity against Leishmania donovani
  作者：Leena Keurulainen、Mikko Heiskari、Satu Nenonen、Abedelmajeed Nasereddin、Dmitry Kopelyanskiy、Teppo O. Leino、Jari Yli-Kauhaluoma、Charles L. Jaffe、Paula Kiuru

  DOI：10.1039/c5md00119f

  日期：——

  Antileishmanial evaluation of 25 derivatives revealed promising inhibition activity.

  25个衍生物的抗利什曼病评估显示出有希望的抑制活性。