6-bromo-1-methyl-3-trityl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one | 1355152-77-0

• 分子结构分类: 有机化合物 - 苯类化合物 - 三苯基化合物
• 英文名称: 6-bromo-1-methyl-3-trityl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one
• 英文别名: 6-bromo-1-methyl-3-tritylimidazo[4,5-b]pyridin-2-one
• CAS: 1355152-77-0
• 化学式: C₂₆H₂₀BrN₃O
• 分子量: 470.368
• InChiKey: ZTSKGNVGCSZGEG-UHFFFAOYSA-N

物化性质

• 沸点：
  598.8±50.0 °C(Predicted)
• 密度：
  1.417±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5.6
• 重原子数：
  31
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.08
• 拓扑面积：
  36.4
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  6-bromo-1-methyl-3-trityl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one 在 potassium phosphate 、 tris-(dibenzylideneacetone)dipalladium(0) 、 N,N-二异丙基乙胺 、 三环己基膦 作用下， 以 1,4-二氧六环 、 二氯甲烷 为溶剂， 反应 3.17h， 生成 N-methyl-3-(1-methyl-2-oxo-3-tritylimidazo[4,5-b]pyridin-6-yl)benzamide
  参考文献：
  名称：

  Structure Guided Development of Novel Thymidine Mimetics Targeting Pseudomonas aeruginosa Thymidylate Kinase: From Hit to Lead Generation

  摘要：

  Thymidylate kinase (TMK) is a potential chemotherapeutic target because it is directly involved in the synthesis of an essential component, thymidine triphosphate, in DNA replication. All reported TMK inhibitors are thymidine analogues, which might retard their development as potent therapeutics due to cell permeability and off-target activity against human TMK. A small molecule hit (1, IC(50) = 58 μM), which has reasonable inhibition potency against Pseudomonas aeruginosa TMK (PaTMK), was identified by the analysis of the binding mode of thymidine or TP(5)A in a PaTMK homology model. This hit (1) was cocrystallized with PaTMK, and several potent PaTMK inhibitors (leads, 46, 47, 48, and 56, IC(50) = 100-200 nM) were synthesized using computer-aided design approaches including virtual synthesis/screening, which was used to guide the design of inhibitors. The binding mode of the optimized leads in PaTMK overlaps with that of other bacterial TMKs but not with human TMK, which shares few common features with the bacterial enzymes. Therefore, the optimized TMK inhibitors described here should be useful for the development of antibacterial agents targeting TMK without undesired off-target effects. In addition, an inhibition mechanism associated with the LID loop, which mimics the process of phosphate transfer from ATP to dTMP, was proposed based on X-ray cocrystal structures, homology models, and structure-activity relationship results.

  DOI：

  10.1021/jm201349f
• 作为产物：
  描述：

  2,3-二氨基-5-溴吡啶 在 吡啶 、 lithium aluminium tetrahydride 、 三乙胺 作用下， 以 四氢呋喃 、 乙醚 、 二氯甲烷 为溶剂， 反应 18.67h， 生成 6-bromo-1-methyl-3-trityl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one
  参考文献：
  名称：

  咪唑并吡啶并酮和7-氮杂恶唑的合成策略及其作为抗菌剂的评价

  摘要：

  已评估了各种合成方法和途径来制备高级咪唑并吡啶并酮和7-氮杂新多烯。研究靶分子作为大肠杆菌胸苷酸单磷酸激酶抑制剂。酶促测定表明咪唑并吡啶并酮是大肠杆菌胸苷单磷酸激酶的活性抑制剂。相反，目标7-氮杂恶唑具有较低的活性。

  DOI：

  10.1002/ejoc.202100172

文献信息

• [EN] METHODS FOR TREATING NEUROLOGICAL DISORDERS<br/>[FR] MÉTHODES DE TRAITEMENT DE TROUBLES NEUROLOGIQUES
  申请人：[en]PROTHENA BIOSCIENCES LIMITED

  公开号：WO2023107714A2

  公开（公告）日：2023-06-15

  This disclosure provides compounds and pharmaceutically acceptable salts thereof, that inhibit Dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A). These chemical entities are useful, e.g., for treating a condition, disease or disorder in which increased (e.g., excessive) DYRK1A activation contributes to the pathology and/or symptoms and/or progression of the condition, disease or disorder (e.g., a neurological disorder) in a subject (e.g., a human). This disclosure also provides compositions containing the same as well as methods of using and making the same.
• Structure Guided Development of Novel Thymidine Mimetics Targeting <i>Pseudomonas aeruginosa</i> Thymidylate Kinase: From Hit to Lead Generation
  作者：Jun Yong Choi、Mark S. Plummer、Jeremy Starr、Charlene R. Desbonnet、Holly Soutter、Jeanne Chang、J. Richard Miller、Keith Dillman、Alita A. Miller、William R. Roush

  DOI：10.1021/jm201349f

  日期：2012.1.26

  Thymidylate kinase (TMK) is a potential chemotherapeutic target because it is directly involved in the synthesis of an essential component, thymidine triphosphate, in DNA replication. All reported TMK inhibitors are thymidine analogues, which might retard their development as potent therapeutics due to cell permeability and off-target activity against human TMK. A small molecule hit (1, IC(50) = 58 μM), which has reasonable inhibition potency against Pseudomonas aeruginosa TMK (PaTMK), was identified by the analysis of the binding mode of thymidine or TP(5)A in a PaTMK homology model. This hit (1) was cocrystallized with PaTMK, and several potent PaTMK inhibitors (leads, 46, 47, 48, and 56, IC(50) = 100-200 nM) were synthesized using computer-aided design approaches including virtual synthesis/screening, which was used to guide the design of inhibitors. The binding mode of the optimized leads in PaTMK overlaps with that of other bacterial TMKs but not with human TMK, which shares few common features with the bacterial enzymes. Therefore, the optimized TMK inhibitors described here should be useful for the development of antibacterial agents targeting TMK without undesired off-target effects. In addition, an inhibition mechanism associated with the LID loop, which mimics the process of phosphate transfer from ATP to dTMP, was proposed based on X-ray cocrystal structures, homology models, and structure-activity relationship results.
• Synthetic Strategies towards Imidazopyridinones and 7‐Azaoxindoles and their Evaluation as Antibacterial Agents
  作者：Fredrik Heen Blindheim、Cecilie Elisabeth Olsen、Caroline Krogh Søgaard、Marit Otterlei、Eirik Sundby、Bård Helge Hoff

  DOI：10.1002/ejoc.202100172

  日期：2021.5.14

  Various synthetic methods and routes have been evaluated to prepare advanced imidazopyridinones and 7‐azaoxindoles. The target molecules were investigated as E. coli thymidylate monophosphate kinase inhibitors. Enzymatic assays showed the imidazopyridinones to be active inhibitors of E. coli thymidylate monophosphate kinase. In contrast the target 7‐azaoxindole demonstrated low activity.

  已评估了各种合成方法和途径来制备高级咪唑并吡啶并酮和7-氮杂新多烯。研究靶分子作为大肠杆菌胸苷酸单磷酸激酶抑制剂。酶促测定表明咪唑并吡啶并酮是大肠杆菌胸苷单磷酸激酶的活性抑制剂。相反，目标7-氮杂恶唑具有较低的活性。