pentafluorophenyl 3-(1-methyl-2-oxo-3-trityl-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)benzoate | 1355152-97-4

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 缩酚酸和缩酚酸环醚类
• 英文名称: pentafluorophenyl 3-(1-methyl-2-oxo-3-trityl-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)benzoate
• 英文别名: (2,3,4,5,6-Pentafluorophenyl) 3-(1-methyl-2-oxo-3-tritylimidazo[4,5-b]pyridin-6-yl)benzoate
• CAS: 1355152-97-4
• 化学式: C₃₉H₂₄F₅N₃O₃
• 分子量: 677.63
• InChiKey: ZBPCGTUIDLDZFG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  8.4
• 重原子数：
  50
• 可旋转键数：
  8
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.05
• 拓扑面积：
  62.7
• 氢给体数：
  0
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  pentafluorophenyl 3-(1-methyl-2-oxo-3-trityl-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)benzoate 在 N,N-二异丙基乙胺 、 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 1.5h， 生成
  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：

  5-溴-N3-甲基吡啶-2,3-二胺 在 potassium phosphate 、 tris-(dibenzylideneacetone)dipalladium(0) 、 三乙胺 、 N,N-二异丙基乙胺 、 三环己基膦 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 二氯甲烷 、 甲苯 为溶剂， 反应 23.17h， 生成 pentafluorophenyl 3-(1-methyl-2-oxo-3-trityl-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)benzoate
  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

文献信息

• 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.