6-bromo-1,4-dihydro-4-oxo-1-(β-D-ribofuranosyl)quinoline-3-carboxylic acid | 224175-75-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: 6-bromo-1,4-dihydro-4-oxo-1-(β-D-ribofuranosyl)quinoline-3-carboxylic acid
• 英文别名: 6-bromo-1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]-4-oxo-quinoline-3-carboxylic acid；6-bromo-1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-4-oxoquinoline-3-carboxylic acid
• CAS: 224175-75-1
• 化学式: C₁₅H₁₄BrNO₇
• 分子量: 400.183
• InChiKey: YLCFGGBOILHPDT-FMKGYKFTSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  24
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  128
• 氢给体数：
  4
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  ethyl 6-bromo-1-(2',3',5'-tri-O-benzoyl-β-D-ribofuranosyl)-4-quinolone-3-carboxylate 在 sodium hydroxide 作用下， 以 乙醇 为溶剂， 生成 6-bromo-1,4-dihydro-4-oxo-1-(β-D-ribofuranosyl)quinoline-3-carboxylic acid
  参考文献：
  名称：

  Molecular design, synthesis and biological evaluation of 1,4-dihydro-4-oxoquinoline ribonucleosides as TcGAPDH inhibitors with trypanocidal activity

  摘要：

  The 1,4-dihydro-4-oxoquinoline ribonucleoside, Neq135, is the first low micromolar trypanosomatidae inhibitor to show good ligand efficiency (0.28 kcal mol(-1) atom(-1)) and good ligand lipophilicity efficiency (0.37 kcal mol(-1) atom(-1)) when acting against Trypanosoma cruzi glyceraldehyde 3-phosphate dehydrogenase (TcGAPDH). This and other six ribonucleosides were synthesized using our in-house technology, and assayed against the GAPDH NAD(+) site using isothermal titration calorimetry (ITC). Compound Neq135 had acceptable in vitro cytotoxicity, inhibited TcGAPDH with a K-i(app) value of 16 mu M and killed the trypomastigote form of Trypanosoma cruzi Tulahuen strain with a concentration similar to that displayed by the control drug benznidazole. Neq135 is tenfold lower kinetic affinity against hGAPDH and does not kill Balb-c fibroblast nor spleen mouse cells. These results emphasize the possibility of integrating ligand- and target-based designs to uncover potent and selective TcGAPDH inhibitors that expands the opportunity for further medicinal chemistry endeavor towards NAD(+) TcGAPDH site. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2013.06.029

文献信息

• Nucleoside hydrolase immobilized on magnetic particles as a tool for onflow screening and characterization of inhibitors
  作者：Pamella Christina Ortega de Oliveira、Millena Santana Ceroullo、Mayane Barbosa dos Santos、Pedro Rodrigues Coelho Medeiros、Bruno Clemente Brandão Marques、Luzineide Wanderley Tinoco、Maria Cecília Bastos Vieira de Souza、Fernanda da Costa Santos Boechat、Marcela Cristina de Moraes

  DOI：10.1016/j.jpba.2023.115589

  日期：2023.10

  immobilized enzyme reactor (IMER). For an automated assay, the LdNH-MP-IMER was connected in-line to an analytical column in an HPLC-DAD system to monitor the enzyme activity through quantification of the product hypoxanthine. Kinetic studies provided a KM value of 2079 ± 87 µmol.L−1 for the inosine substrate. Validation of the LdNH-MP-IMER for onflow screening purposes was performed with a library containing

  核苷水解酶 (NH) 被认为是开发新型抗原虫剂的目标。用于鉴定 NH 抑制剂的新型自动化筛选方法的开发可以加速药物发现过程的第一阶段。在这项工作中，来自杜氏利什曼原虫的 NH(LdNH) 被共价固定到磁性颗粒 (LdNH-MPs) 上，并被磁铁捕获到 TFE 管中，形成固定化酶反应器 (IMER)。对于自动测定，Ld NH-MP-IMER 串联连接至 HPLC-DAD 系统中的分析柱，通过产物次黄嘌呤的定量来监测酶活性。动力学研究得出肌苷底物的K M值为 2079 ± 87 µmol.L-1使用含有 12 种喹诺酮核糖核苷的文库对LdNH-MP-IMER 进行流动筛选验证。其中，3个被鉴定为新型竞争性LdNH抑制剂，Ki值在83.5至169.4 µmol.L-1。这种新颖的在线筛选测定已被证明可靠、快速、低成本，并且适用于大型化合物库。
• Molecular design, synthesis and biological evaluation of 1,4-dihydro-4-oxoquinoline ribonucleosides as TcGAPDH inhibitors with trypanocidal activity
  作者：Fabyana A. Soares、Renata Sesti-Costa、João Santana da Silva、Maria Cecília B.V. de Souza、Vitor F. Ferreira、Fernanda da C. Santos、Patricia A.U. Monteiro、Andrei Leitão、Carlos A. Montanari

  DOI：10.1016/j.bmcl.2013.06.029

  日期：2013.8

  The 1,4-dihydro-4-oxoquinoline ribonucleoside, Neq135, is the first low micromolar trypanosomatidae inhibitor to show good ligand efficiency (0.28 kcal mol(-1) atom(-1)) and good ligand lipophilicity efficiency (0.37 kcal mol(-1) atom(-1)) when acting against Trypanosoma cruzi glyceraldehyde 3-phosphate dehydrogenase (TcGAPDH). This and other six ribonucleosides were synthesized using our in-house technology, and assayed against the GAPDH NAD(+) site using isothermal titration calorimetry (ITC). Compound Neq135 had acceptable in vitro cytotoxicity, inhibited TcGAPDH with a K-i(app) value of 16 mu M and killed the trypomastigote form of Trypanosoma cruzi Tulahuen strain with a concentration similar to that displayed by the control drug benznidazole. Neq135 is tenfold lower kinetic affinity against hGAPDH and does not kill Balb-c fibroblast nor spleen mouse cells. These results emphasize the possibility of integrating ligand- and target-based designs to uncover potent and selective TcGAPDH inhibitors that expands the opportunity for further medicinal chemistry endeavor towards NAD(+) TcGAPDH site. (C) 2013 Elsevier Ltd. All rights reserved.