ethyl 3-(3-(4-methoxyphenyl)thioureido)-1H-indole-2-carboxylate | 686736-60-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: ethyl 3-(3-(4-methoxyphenyl)thioureido)-1H-indole-2-carboxylate
• 英文别名: ethyl 3-[(4-methoxyphenyl)carbamothioylamino]-1H-indole-2-carboxylate
• CAS: 686736-60-7
• 化学式: C₁₉H₁₉N₃O₃S
• 分子量: 369.444
• InChiKey: VYQIEPFRPAVEKS-UHFFFAOYSA-N

物化性质

• 熔点：
  181-182 °C(Solv: ethanol (64-17-5))
• 沸点：
  560.6±60.0 °C(Predicted)
• 密度：
  1.375±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  26
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.16
• 拓扑面积：
  108
• 氢给体数：
  3
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  ethyl 3-(3-(4-methoxyphenyl)thioureido)-1H-indole-2-carboxylate 在 sodium ethanolate 、 乙酰氯 作用下， 以 乙醇 为溶剂， 反应 12.0h， 生成 3-(4-Methoxyphenyl)-2-sulfanylidene-1,5-dihydropyrimido[5,4-b]indol-4-one
  参考文献：
  名称：

  Identification of Biologically Active Pyrimido[5,4-b]indoles That Prolong NF-κB Activation without Intrinsic Activity

  摘要：

  Most vaccine adjuvants directly stimulate and activate antigen presenting cells but do not sustain immunostimulation of these cells. A high throughput screening (HTS) strategy was designed to identify compounds that would sustain NF-kappa B activation by a stimulus from the Toll-like receptor (TLR)4 ligand, lipopolysaccharide (LPS). Several pilot studies optimized the parameters and conditions for a cell based NF-kappa B reporter assay in human monocytic THP-1 cells. The final assay evaluated prolongation of LPS induced NF-kappa B activation at 12 h. The dynamic range of the assay was confirmed in a pilot screen of 14 631 compounds and subsequently in a main extensive screen with 166 304 compounds. Hit compounds were identified using an enrichment strategy based on unsupervised chemoinformatic clustering, and also by a naive "Top X" approach. A total of 2011 compounds were then rescreened for levels of coactivation with LPS at 5 h and 12 h, which provided kinetic profiles. Of the 407 confirmed hits, compounds that showed correlation of the kinetic profiles with the structural similarities led to identification of four chemotypes: pyrimido[5,4-b]indoles, 4H-chromene-3-carbonitriles, benzo[d][1,3]dioxol-2-ylureas, and tetrahydrothieno[2,3-c]pyridines, which were segregated by 5 h and 12 h kinetic characteristics. Unlike the TLR4 agonistic pyrimidoindoles identified in previous studies, the revealed pyrimidoindoles in the present work did not intrinsically stimulate TLR4 nor induce NF-kappa B but rather prolonged NF-kappa B signaling induced by LPS. A 42-member combinatorial library was synthesized which led to identification of potent N3-alkyl substituted pyrimidoindoles that were not only active in vitro but also enhanced antibody responses in vivo when used as a coadjuvant. The novel HTS strategy led to identification of compounds that are intrinsically quiescent but functionally prolong stimulation by a TLR4 ligand and thereby potentiate vaccine efficacy.

  DOI：

  10.1021/acscombsci.7b00080
• 作为产物：
  描述：

  3-氨基-2-吲哚羧酸乙酯 、 4-甲氧基苯基 异硫氰酸酯 反应 0.5h， 以65%的产率得到ethyl 3-(3-(4-methoxyphenyl)thioureido)-1H-indole-2-carboxylate
  参考文献：
  名称：

  使用Lawesson试剂对4,5-二氢-1,3-噻嗪[5,4-b]吲哚衍生物进行一步封闭。第五个二氢-1,3-噻嗪[b]吲哚异构体

  摘要：

  我们报告了一种合成新环系统的简便方法：4,5-二氢-1,3-噻嗪基[5,4- b ]吲哚。该程序涉及在二氧化硅存在下使用Lawesson试剂，以实现2-苯甲酰基氨基-3-羟甲基吲哚中间体的一步闭环反应，从而提供4,5-二氢-2--2-芳基-1,3-噻嗪基[ 5,4‐ b ]吲哚。通过相应的3-苯基硫脲-2-羧酸酯衍生物，通过化学选择性还原酯基，然后在酸性条件下闭环，可得到2-苯基亚氨基-1,3-噻嗪[5,4- b ]吲哚。红外，1 H-NMR和13阐明了新产品的结构C-NMR光谱，包括2D-HMQC，2D-HMBC和DEPT测量。J.杂环化​​学。（2011）。

  DOI：

  10.1002/jhet.607

文献信息

• One-step ring-closure procedure for 4,5-dihydro-1,3-thiazino[5,4-b]indole derivatives with Lawesson's reagent. The fifth dihydro-1,3-thiazino[b]indole isomer
  作者：Péter Csomós、Lajos Fodor、Gábor Bernáth、Antal Csámpai、Pál Sohár

  DOI：10.1002/jhet.607

  日期：2011.9

  corresponding 3‐phenylthiourea‐2‐carboxylic acid ester derivatives by chemoselective reduction of the ester group, followed by ring closure under acidic conditions. The structures of the novel products were elucidated by IR, 1H‐NMR, and 13C‐NMR spectroscopy, including 2D‐HMQC, 2D‐HMBC, and DEPT measurements. J. Heterocyclic Chem., (2011).

  我们报告了一种合成新环系统的简便方法：4,5-二氢-1,3-噻嗪基[5,4- b ]吲哚。该程序涉及在二氧化硅存在下使用Lawesson试剂，以实现2-苯甲酰基氨基-3-羟甲基吲哚中间体的一步闭环反应，从而提供4,5-二氢-2--2-芳基-1,3-噻嗪基[ 5,4‐ b ]吲哚。通过相应的3-苯基硫脲-2-羧酸酯衍生物，通过化学选择性还原酯基，然后在酸性条件下闭环，可得到2-苯基亚氨基-1,3-噻嗪[5,4- b ]吲哚。红外，1 H-NMR和13阐明了新产品的结构C-NMR光谱，包括2D-HMQC，2D-HMBC和DEPT测量。J.杂环化​​学。（2011）。
• Identification of Biologically Active Pyrimido[5,4-<i>b</i>]indoles That Prolong NF-κB Activation without Intrinsic Activity
  作者：Michael Chan、Alast Ahmadi、Shiyin Yao、Fumi Sato-Kaneko、Karen Messer、Minya Pu、Brandon Nguyen、Tomoko Hayashi、Maripat Corr、Dennis A. Carson、Howard B. Cottam、Nikunj M. Shukla

  DOI：10.1021/acscombsci.7b00080

  日期：2017.8.14

  Most vaccine adjuvants directly stimulate and activate antigen presenting cells but do not sustain immunostimulation of these cells. A high throughput screening (HTS) strategy was designed to identify compounds that would sustain NF-kappa B activation by a stimulus from the Toll-like receptor (TLR)4 ligand, lipopolysaccharide (LPS). Several pilot studies optimized the parameters and conditions for a cell based NF-kappa B reporter assay in human monocytic THP-1 cells. The final assay evaluated prolongation of LPS induced NF-kappa B activation at 12 h. The dynamic range of the assay was confirmed in a pilot screen of 14 631 compounds and subsequently in a main extensive screen with 166 304 compounds. Hit compounds were identified using an enrichment strategy based on unsupervised chemoinformatic clustering, and also by a naive "Top X" approach. A total of 2011 compounds were then rescreened for levels of coactivation with LPS at 5 h and 12 h, which provided kinetic profiles. Of the 407 confirmed hits, compounds that showed correlation of the kinetic profiles with the structural similarities led to identification of four chemotypes: pyrimido[5,4-b]indoles, 4H-chromene-3-carbonitriles, benzo[d][1,3]dioxol-2-ylureas, and tetrahydrothieno[2,3-c]pyridines, which were segregated by 5 h and 12 h kinetic characteristics. Unlike the TLR4 agonistic pyrimidoindoles identified in previous studies, the revealed pyrimidoindoles in the present work did not intrinsically stimulate TLR4 nor induce NF-kappa B but rather prolonged NF-kappa B signaling induced by LPS. A 42-member combinatorial library was synthesized which led to identification of potent N3-alkyl substituted pyrimidoindoles that were not only active in vitro but also enhanced antibody responses in vivo when used as a coadjuvant. The novel HTS strategy led to identification of compounds that are intrinsically quiescent but functionally prolong stimulation by a TLR4 ligand and thereby potentiate vaccine efficacy.