(2-amino-4-phenylthiazol-5-yl)(morpholino)methanone

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 恶嗪烷类
• 英文名称: (2-amino-4-phenylthiazol-5-yl)(morpholino)methanone
• 英文别名: (2-Amino-4-phenyl-1,3-thiazol-5-yl)-morpholin-4-ylmethanone
• 化学式: C₁₄H₁₅N₃O₂S
• 分子量: 289.358
• InChiKey: KEZQAXOSORPHFD-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  20
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  96.7
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  1-(1,3-苯并二氧代l-5-基)环丙烷羧酸 、 (2-amino-4-phenylthiazol-5-yl)(morpholino)methanone 在 N,N-二异丙基乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 18.08h， 生成 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-(morpholine-4-carbonyl)-4-phenylthiazol-2-yl)cyclopropanecarboxamide
  参考文献：
  名称：

  Discovery of novel VX-809 hybrid derivatives as F508del-CFTR correctors by molecular modeling, chemical synthesis and biological assays

  摘要：

  Cystic fibrosis (CF) is the autosomal recessive disorder most recurrent in Caucasian populations. It is caused by different mutations in the cystic fibrosis transmembrane regulator protein (CFTR) gene, with F508del being the most common. During the last years, small-molecule therapy chosen to contrast CF relied on compounds that correct CFTR misfolding and ER retention (correctors such as VX-809), or defective channel gating (potentiators such as VX-770). Combination therapy with the two series of drugs has been applied, leading to the approval of several multi-drugs such as Orkambi. Despite this, this treatment proved to be only partially effective making the search for novel modulators an urgent need to contrast CF. Recently, we reported compound 2a as reference compound of a series of aminoarylthiazole-VX-809 hybrid derivatives exhibiting promising F508del-CFTR corrector ability. Herein, we report exploring the docking mode of the prototype VX-809 and of 2a in order to derive useful guidelines for the rational design of novel optimized analogues. To demonstrate experimentally their effective F508del-CFTR-binding and rescuing potential, the most promising derivatives had been synthesized and evaluated in biological assays including YFP functional assay on F508del-CFTR CFBE41o-cells, trans epithelial electrical resistance (TEER) and surface plasmon resonance (SPR). This multidisciplinary strategy led to the discovery of a second series of hybrids including 7j and 7m endowed with higher potency than the prototype.

  DOI：

  10.1016/j.ejmech.2020.112833
• 作为产物：
  描述：

  N-(bis(4-methoxybenzyl)carbamothioyl)benzamide 在 三氟乙酸 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 38.0h， 生成 (2-amino-4-phenylthiazol-5-yl)(morpholino)methanone
  参考文献：
  名称：

  Discovery of novel VX-809 hybrid derivatives as F508del-CFTR correctors by molecular modeling, chemical synthesis and biological assays

  摘要：

  Cystic fibrosis (CF) is the autosomal recessive disorder most recurrent in Caucasian populations. It is caused by different mutations in the cystic fibrosis transmembrane regulator protein (CFTR) gene, with F508del being the most common. During the last years, small-molecule therapy chosen to contrast CF relied on compounds that correct CFTR misfolding and ER retention (correctors such as VX-809), or defective channel gating (potentiators such as VX-770). Combination therapy with the two series of drugs has been applied, leading to the approval of several multi-drugs such as Orkambi. Despite this, this treatment proved to be only partially effective making the search for novel modulators an urgent need to contrast CF. Recently, we reported compound 2a as reference compound of a series of aminoarylthiazole-VX-809 hybrid derivatives exhibiting promising F508del-CFTR corrector ability. Herein, we report exploring the docking mode of the prototype VX-809 and of 2a in order to derive useful guidelines for the rational design of novel optimized analogues. To demonstrate experimentally their effective F508del-CFTR-binding and rescuing potential, the most promising derivatives had been synthesized and evaluated in biological assays including YFP functional assay on F508del-CFTR CFBE41o-cells, trans epithelial electrical resistance (TEER) and surface plasmon resonance (SPR). This multidisciplinary strategy led to the discovery of a second series of hybrids including 7j and 7m endowed with higher potency than the prototype.

  DOI：

  10.1016/j.ejmech.2020.112833

文献信息

• 一种4,5-二取代-2-氨基噻唑类化合物的合成方法
  申请人：沈阳药科大学

  公开号：CN114057666B

  公开（公告）日：2023-02-07

  本发明属于有机合成及药物合成领域，具体是一种4,5‑二取代‑2‑氨基噻唑类化合物的合成方法。本发明提供下述技术方案：在有机溶剂或水中，氧气(或空气)氛围下，以具有如式(I)所示结构的酮类化合物与式(II)所示结构的硫脲或硫脲衍生物为反应原料，在活性炭和金属盐共同催化作用下，通过缩合/氧化偶联反应得到式(III)所示结构的4,5‑二取代‑2‑氨基噻唑类化合物，所述的反应过程可用以下反应方程式表示。
• Discovery of novel VX-809 hybrid derivatives as F508del-CFTR correctors by molecular modeling, chemical synthesis and biological assays
  作者：Alice Parodi、Giada Righetti、Emanuela Pesce、Annalisa Salis、Bruno Tasso、Chiara Urbinati、Valeria Tomati、Gianluca Damonte、Marco Rusnati、Nicoletta Pedemonte、Elena Cichero、Enrico Millo

  DOI：10.1016/j.ejmech.2020.112833

  日期：2020.12

  Cystic fibrosis (CF) is the autosomal recessive disorder most recurrent in Caucasian populations. It is caused by different mutations in the cystic fibrosis transmembrane regulator protein (CFTR) gene, with F508del being the most common. During the last years, small-molecule therapy chosen to contrast CF relied on compounds that correct CFTR misfolding and ER retention (correctors such as VX-809), or defective channel gating (potentiators such as VX-770). Combination therapy with the two series of drugs has been applied, leading to the approval of several multi-drugs such as Orkambi. Despite this, this treatment proved to be only partially effective making the search for novel modulators an urgent need to contrast CF. Recently, we reported compound 2a as reference compound of a series of aminoarylthiazole-VX-809 hybrid derivatives exhibiting promising F508del-CFTR corrector ability. Herein, we report exploring the docking mode of the prototype VX-809 and of 2a in order to derive useful guidelines for the rational design of novel optimized analogues. To demonstrate experimentally their effective F508del-CFTR-binding and rescuing potential, the most promising derivatives had been synthesized and evaluated in biological assays including YFP functional assay on F508del-CFTR CFBE41o-cells, trans epithelial electrical resistance (TEER) and surface plasmon resonance (SPR). This multidisciplinary strategy led to the discovery of a second series of hybrids including 7j and 7m endowed with higher potency than the prototype.