(S)-5-((1H-indol-3-yl)methyl)-1-acetyl-2-thioxoimidazolidin-4-one | 182002-62-6

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (S)-5-((1H-indol-3-yl)methyl)-1-acetyl-2-thioxoimidazolidin-4-one
• 英文别名: (5S)-1-acetyl-5-(1H-indol-3-ylmethyl)-2-thiohydantoin；1-acetyl-5-((1H-indol-3-yl)methyl)-2-thioxoimidazolidin-4-one；(5S)-1-acetyl-5-(1H-indol-3-ylmethyl)-2-thioxoimidazolidin-4-one；(5S)-1-acetyl-5-(1H-indol-3-ylmethyl)-2-sulfanylideneimidazolidin-4-one
• CAS: 182002-62-6
• 化学式: C₁₄H₁₃N₃O₂S
• 分子量: 287.342
• InChiKey: DNYULDHSNOLVOZ-LBPRGKRZSA-N

物化性质

• 密度：
  1.45±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  20
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  97.3
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  (S)-5-((1H-indol-3-yl)methyl)-1-acetyl-2-thioxoimidazolidin-4-one 在 potassium carbonate 、 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 、 三乙胺 作用下， 以 乙醇 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 24.25h， 生成 4-({[(±)-1-acetyl-5-(1H-indol-3-ylmethyl)-4-oxo-4,5-dihydro-1H-imidazol-2-yl]amino}methyl)-N-(2-aminophenyl)benzamide
  参考文献：
  名称：

  Discovery of Potent, Isoform-Selective Inhibitors of Histone Deacetylase Containing Chiral Heterocyclic Capping Groups and a N-(2-Aminophenyl)benzamide Binding Unit

  摘要：

  The synthesis of a novel series of potent chiral inhibitors of histone deacetylase (HDAC) is described that contain a heterocyclic capping group and a N-(2-aminophenyl)benzamide unit that binds in the active site. In vitro assays for the inhibition of HDAC1, HDAC2, HDAC3-NCoR1, and HDAC8 by the N-(2-aminophenyl)benzmide 24a gave respective IC50 values of 930, 85, 12, and 4100 nM, exhibiting class I selectivity and potent inhibition of HDAC3-NCoR1. Both imidazolinone and thiazoline rings are shown to be effective replacements for the pyrimidine ring present in many other 2-(aminophenyl)benzamides previously reported, an example of each ring system at 1 mu M causing an increase in histone H3K9 acetylation in the human cell lines Jurkat and HeLa and an increase in cell death consistent with induction of apoptosis. Inhibition of the growth of MCF-7, A549, DU145, and HCT116 cell lines by 24a was observed, with respective IC50 values of 5.4, 5.8, 6.4, and 2.2 mM.

  DOI：

  10.1021/jm400634n
• 作为产物：
  描述：

  sodium thiocyanide 、 乙酸酐 、 N-乙酰-L-色氨酸 以 溶剂黄146 为溶剂， 反应 0.5h， 以95%的产率得到(S)-5-((1H-indol-3-yl)methyl)-1-acetyl-2-thioxoimidazolidin-4-one
  参考文献：
  名称：

  Duggan, Brendan M.; Laslett, Robert L.; Wilshire, John F. K., Australian Journal of Chemistry, 1996, vol. 49, # 5, p. 541 - 550

  摘要：

  DOI：

文献信息

• Privileged Scaffolds or Promiscuous Binders: A Comparative Study on Rhodanines and Related Heterocycles in Medicinal Chemistry
  作者：Thomas Mendgen、Christian Steuer、Christian D. Klein

  DOI：10.1021/jm201243p

  日期：2012.1.26

  campaigns, we decided to perform a systematic study on their promiscuity. An amount of 163 rhodanines, hydantoins, thiohydantoins, and thiazolidinediones were synthesized and tested against several targets. The compounds were also characterized with respect to aggregation and electrophilic reactivity, and the binding modes of rhodanines and related compounds in published X-ray cocrystal structures were analyzed

  罗丹宁和具有多个杂原子的相关五元杂环最近因在筛选活动中表现为“频繁的杀手”而成为非选择性化合物，因此在药物发现中几乎没有价值。但是，这种判断似乎主要是基于轶事证据。在筛选活动中鉴定出多种罗丹宁和相关化合物后，我们决定对它们的滥交进行系统的研究。合成了163种罗丹宁，乙内酰脲，硫代乙内酰脲和噻唑烷二酮，并针对几个目标进行了测试。还针对聚集和亲电反应性对化合物进行了表征，并分析了罗丹宁与相关化合物在已发表的X射线共晶结构中的结合模式。结果表明，环外，若丹宁和硫代乙内酰脲中的双键硫原子除具有其他结构特征外，还为极性相互作用和氢键提供了特别高的相互作用位点密度。这会导致“筛选范围”内浓度的混杂行为，但不应视为将此类筛选命中排除在进一步开发之外的一般剔除标准。建议将针对靶标亲和力和选择性的特殊标准应用于这些类型的化合物，并因此以有用的方式利用其特殊和潜在有价值的生物分子结合特性。这会导致“筛选范围”
• Thiohydantoins: Selective N- and S-Functionalization for Liebeskind-Srogl Reaction Study
  作者：Arnaud Tatibouët、Sandrine Gosling、Patrick Rollin

  DOI：10.1055/s-0030-1260259

  日期：2011.11

  Thiohydantoins formed by the Schlack-Kumpf protocol were selectively functionalized at the nitrogen, sulfur, or carbon atom to test the Liebeskind-Srogl reaction possibilities.

  通过 Schlack-Kumpf 方案形成的乙内酰硫脲在氮、硫或碳原子上选择性官能化，以测试 Liebeskind-Srogl 反应的可能性。
• Investigation of the antileishmanial activity and mechanisms of action of acetyl-thiohydantoins
  作者：Bruna Taciane da Silva Bortoleti、Manoela Daiele Gonçalves、Fernanda Tomiotto-Pellissier、Priscila Goes Camargo、João Paulo Assolini、Virginia Marcia Concato、Mariana Barbosa Detoni、Danielle Larazin Bidóia、Marcelle de Lima Ferreira Bispo、Camilo Henrique da Silva Lima、Fernando Cesar de Macedo、Ivete Conchon-Costa、Milena Menegazzo Miranda-Sapla、Pryscilla Fanini Wowk、Wander Rogério Pavanelli

  DOI：10.1016/j.cbi.2021.109690

  日期：2022.1

  sheep erythrocytes. In silico and in vitro analyses showed that acetyl-thiohydantoins exerted in vitro antileishmanial effects on L. amazonensis promastigotes in apoptosis-like and amastigote forms by inducing ROS production and reducing TNF-α levels, indicating that they are good candidates for drug discovery studies in leishmaniasis treatment. Additionally, we carried out molecular docking analyses of

  目前可用的利什曼病治疗方案与高成本、严重副作用和高毒性有关。在以前的研究中，乙内酰脲显示出一些药理活性，并被证明是具有抗利什曼原虫特性的潜在命中化合物。 本研究进一步探讨了乙酰乙内酰脲对亚马逊利什曼原虫的抗利什曼原虫作用并确定了寄生虫死亡的主要过程。我们观察到，与乙内酰脲核相比，乙酰乙内酰脲治疗抑制了前鞭毛体的增殖。这种治疗引起细胞周期进程和寄生虫大小的改变，并引起形态和超微结构的变化。然后我们研究了原生动物死亡的机制；ROS 产生、磷脂酰丝氨酸暴露和质膜透化增加，线粒体膜电位丧失，导致脂质体积聚，并在这些寄生虫上形成自噬泡，并证实了类似细胞凋亡的过程。在细胞内无鞭毛体中，选定的乙酰-乙内酰脲通过增加 ROS 产生和降低 TNF-α 水平来降低感染巨噬细胞的百分比和无鞭毛体/巨噬细胞的数量。此外，乙内酰脲不会在鼠巨噬细胞 (J774A.1)、人单核细胞 (THP-1) 或绵羊红细胞中诱导细
• Casagranda, Franca; Duggan, Brendan M.; Kirkpatrick, Alan, Australian Journal of Chemistry, 1996, vol. 49, # 5, p. 551 - 560
  作者：Casagranda, Franca、Duggan, Brendan M.、Kirkpatrick, Alan、Laslett, Robert L.、Wilshire, John F.K.

  DOI：——

  日期：——
• Discovery of Potent, Isoform-Selective Inhibitors of Histone Deacetylase Containing Chiral Heterocyclic Capping Groups and a <i>N</i>-(2-Aminophenyl)benzamide Binding Unit
  作者：Charles M. Marson、Christopher J. Matthews、Elena Yiannaki、Stephen J. Atkinson、Peter E. Soden、Lena Shukla、Nermina Lamadema、N. Shaun B. Thomas

  DOI：10.1021/jm400634n

  日期：2013.8.8

  The synthesis of a novel series of potent chiral inhibitors of histone deacetylase (HDAC) is described that contain a heterocyclic capping group and a N-(2-aminophenyl)benzamide unit that binds in the active site. In vitro assays for the inhibition of HDAC1, HDAC2, HDAC3-NCoR1, and HDAC8 by the N-(2-aminophenyl)benzmide 24a gave respective IC50 values of 930, 85, 12, and 4100 nM, exhibiting class I selectivity and potent inhibition of HDAC3-NCoR1. Both imidazolinone and thiazoline rings are shown to be effective replacements for the pyrimidine ring present in many other 2-(aminophenyl)benzamides previously reported, an example of each ring system at 1 mu M causing an increase in histone H3K9 acetylation in the human cell lines Jurkat and HeLa and an increase in cell death consistent with induction of apoptosis. Inhibition of the growth of MCF-7, A549, DU145, and HCT116 cell lines by 24a was observed, with respective IC50 values of 5.4, 5.8, 6.4, and 2.2 mM.