4-cyclohexyl-5-(pyridin-2-yl)-4H-1,2,4-triazole-3-thiol

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: 4-cyclohexyl-5-(pyridin-2-yl)-4H-1,2,4-triazole-3-thiol
• 英文别名: 4-cyclohexyl-3-pyridin-2-yl-1H-1,2,4-triazole-5-thione
• 化学式: C₁₃H₁₆N₄S
• mdl: MFCD11543604
• 分子量: 260.363
• InChiKey: DFKYTLSQSXZICI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  18
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.461
• 拓扑面积：
  72.6
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  1-(2-溴乙氧基)-4-氯苯 、 4-cyclohexyl-5-(pyridin-2-yl)-4H-1,2,4-triazole-3-thiol 在 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 为溶剂， 反应 96.0h， 以85%的产率得到2-(5-(2-(4-chlorophenoxy)ethylthio)-4-cyclohexyl-4H-1,2,4-triazol-3-yl)pyridine
  参考文献：
  名称：

  Approaches to design non-covalent inhibitors for human granzyme B (hGrB)

  摘要：

  针对人类颗粒酶B的非共价小分子抑制剂进行了一项基于结构的设计活动，采用了一种虚拟筛选策略，结合三个约束条件和FTMAP探针位点映射，以识别配体“热点”。此外，随后利用ROCS基于形状的叠加方法探索了多样结构的新骨架，接着进行了Glide SP对接、诱导适合对接及QikProp分子性质分析。识别出来自商业可获取库的新型中等活性小分子拮抗剂（IC50值≥25 μM），并通过多步骤合成了三种新骨架。此外，我们提供了一个全面的结构基础药物发现方法的例子，用于非共价抑制剂，该方法依赖于共价结合配体的X射线结构，并指出设计路径可能会因替代和未知的结合姿势而受到影响。

  DOI：

  10.1039/c4ob01874e
• 作为产物：
  描述：

  2-吡啶甲酸乙酯 在 一水合肼 、 sodium hydroxide 作用下， 以 乙醇 为溶剂， 反应 5.0h， 生成 4-cyclohexyl-5-(pyridin-2-yl)-4H-1,2,4-triazole-3-thiol
  参考文献：
  名称：

  Synthesis and anti-endoplasmic reticulum stress activity of N-substituted-2-arylcarbonylhydrazinecarbothioamides

  摘要：

  Misfolded or unfolded proteins are accumulated in lumen of endoplasmic reticulum (ER) in ER stress condition. It has been implicated in many pathological conditions such as Alzheimer's disease, diabetic retinopathy, atherosclerosis, beta-cell apoptosis and lung inflammation. We found a series of N-substituted-2-arylcarbonylhydrazinecarbothioamides to potently decrease ER stress signal, showing up to almost 300-fold better activity than 1-hydroxynaphthoic acid and tauro-ursodesoxycholic acid, positive controls, respectively. Structure-activity relationship (SAR) study showed that 2-arylcarbonyl moiety is critical for the activity of the hydrazinecarbothioamide analogues and side chains tethering on thioamide moiety were relatively insensitive to the activity. Some analogues were found to consistently exert the potency under more physiologically relevant condition where ER stress was induced by palmitic acid. ER stress markers such as CHOP and phosphorylated eIF2 alpha and PERK were accordingly decreased in western blotting upon treatment of compound 4h. Potential ER stress inhibitory activity and novel structures could provide a novel platform for new chemical chaperone and therapy for protein misfolding diseases.

  DOI：

  10.1007/s00044-019-02442-1

文献信息

• Approaches to design non-covalent inhibitors for human granzyme B (hGrB)
  作者：Mi-Sun Kim、Lauriane A. Buisson、Dean A. Heathcote、Haipeng Hu、D. Christopher Braddock、Anthony G. M. Barrett、Philip G. Ashton-Rickardt、James P. Snyder

  DOI：10.1039/c4ob01874e

  日期：——

  A structure-based design campaign for non-covalent small molecule inhibitors of human granzyme B was carried out by means of a virtual screening strategy employing three constraints and probe site-mapping with FTMAP to identify ligand “hot spots”. In addition, new scaffolds of diverse structures were subsequently explored with ROCS shape-based superposition methods, following by Glide SP docking, induced fit docking and analysis of QikProp molecular properties. Novel classes of moderately active small molecule blockers (≥25 μM IC50 values) from commercially available libraries were identified, and three novel scaffolds have been synthesized by multi-step procedures. Furthermore, we provide an example of a comprehensive structure-based drug discovery approach to non-covalent inhibitors that relies on the X-ray structure of a covalently bound ligand and suggest that the design path may be compromised by alternative and unknown binding poses.

  针对人类颗粒酶B的非共价小分子抑制剂进行了一项基于结构的设计活动，采用了一种虚拟筛选策略，结合三个约束条件和FTMAP探针位点映射，以识别配体“热点”。此外，随后利用ROCS基于形状的叠加方法探索了多样结构的新骨架，接着进行了Glide SP对接、诱导适合对接及QikProp分子性质分析。识别出来自商业可获取库的新型中等活性小分子拮抗剂（IC50值≥25 μM），并通过多步骤合成了三种新骨架。此外，我们提供了一个全面的结构基础药物发现方法的例子，用于非共价抑制剂，该方法依赖于共价结合配体的X射线结构，并指出设计路径可能会因替代和未知的结合姿势而受到影响。
• Synthesis and anti-endoplasmic reticulum stress activity of N-substituted-2-arylcarbonylhydrazinecarbothioamides
  作者：Hoon Choi、Wheesahng Yun、Jung-hun Lee、Seoul Jang、Sang Won Park、Dong Hwan Kim、Kyoung Pyo Seon、Jung-mi Hyun、Kwiwan Jeong、Jin-mo Ku、Tae-gyu Nam

  DOI：10.1007/s00044-019-02442-1

  日期：2019.12

  Misfolded or unfolded proteins are accumulated in lumen of endoplasmic reticulum (ER) in ER stress condition. It has been implicated in many pathological conditions such as Alzheimer's disease, diabetic retinopathy, atherosclerosis, beta-cell apoptosis and lung inflammation. We found a series of N-substituted-2-arylcarbonylhydrazinecarbothioamides to potently decrease ER stress signal, showing up to almost 300-fold better activity than 1-hydroxynaphthoic acid and tauro-ursodesoxycholic acid, positive controls, respectively. Structure-activity relationship (SAR) study showed that 2-arylcarbonyl moiety is critical for the activity of the hydrazinecarbothioamide analogues and side chains tethering on thioamide moiety were relatively insensitive to the activity. Some analogues were found to consistently exert the potency under more physiologically relevant condition where ER stress was induced by palmitic acid. ER stress markers such as CHOP and phosphorylated eIF2 alpha and PERK were accordingly decreased in western blotting upon treatment of compound 4h. Potential ER stress inhibitory activity and novel structures could provide a novel platform for new chemical chaperone and therapy for protein misfolding diseases.