9-[2,5-dideoxy-2-fluoro-5-[N-(N-2-hydroxybenzoyl)sulfamoyl]amino-β-D-ribofuranosyl]adenine triethylammonium salt

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 2 '，5'-二脱氧核苷
• 英文名称: 9-[2,5-dideoxy-2-fluoro-5-[N-(N-2-hydroxybenzoyl)sulfamoyl]amino-β-D-ribofuranosyl]adenine triethylammonium salt
• 英文别名: 5′-N-[N-(2-hydroxybenzoyl)sulfamoyl]amino-2′,5′-dideoxy-2′-fluoroadenosine triethylammonium Salt；2'-deoxy-2'-fluoro-5'-O-[N-(salicyl)sulfamoyl]adenosine triethylammonium；N-[[(2R,3R,4R,5R)-5-(6-aminopurin-9-yl)-4-fluoro-3-hydroxyoxolan-2-yl]methylsulfamoyl]-2-hydroxybenzamide;N,N-diethylethanamine
• 化学式: C₆H₁₅N*C₁₇H₁₈FN₇O₆S
• 分子量: 568.629
• InChiKey: XPWFJUXDKDBNIV-JNOJLDNUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.32
• 重原子数：
  39
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  206
• 氢给体数：
  5
• 氢受体数：
  13

反应信息

• 作为产物：
  描述：

  2'-氟-2'-脱氧腺苷 在 吡啶 、 盐酸 、 4-二甲氨基吡啶 、 sodium azide 、 15-冠醚-5 、 叠氮磷酸二苯酯 、 sodium hydride 、 磺酰胺 、 caesium carbonate 、 溶剂黄146 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 、 三氟乙酸 、 锌 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 57.17h， 生成 9-[2,5-dideoxy-2-fluoro-5-[N-(N-2-hydroxybenzoyl)sulfamoyl]amino-β-D-ribofuranosyl]adenine triethylammonium salt
  参考文献：
  名称：

  Investigation and Conformational Analysis of Fluorinated Nucleoside Antibiotics Targeting Siderophore Biosynthesis

  摘要：

  Antibiotic resistance represents one of the greatest threats to public health. The adenylation inhibitor 5'-O-[N-(salicyl)sulfamoyl]adenosine (SAL-AMS) is the archetype for a new class of nucleoside antibiotics that target iron acquisition in pathogenic microorganisms and is especially effective against Mycobacterium tuberculosis, the causative agent of tuberculosis. Strategic incorporation of fluorine at the 2' and 3' positions of the nucleoside was performed by direct fluorination to enhance activity and improve drug disposition properties. The resulting SAL-AMS analogues were comprehensively assessed for biochemical potency, whole-cell antitubercular activity, and in vivo pharmacokinetic parameters. Conformational analysis suggested a strong preference of fluorinated sugar rings for either a 2'-endo, 3'-exo (South), or a 3'-endo,2'-exo (North) conformation. The structureactivity relationships revealed a strong conformational bias for the C3'-endo conformation to maintain potent biochemical and whole-cell activity, whereas improved pharmacokinetic properties were associated with the C2'-endo conformation.

  DOI：

  10.1021/acs.joc.5b00550

文献信息

• Synthesis and Pharmacokinetic Evaluation of Siderophore Biosynthesis Inhibitors for <i>Mycobacterium tuberculosis</i>
  作者：Kathryn M. Nelson、Kishore Viswanathan、Surendra Dawadi、Benjamin P. Duckworth、Helena I. Boshoff、Clifton E. Barry、Courtney C. Aldrich

  DOI：10.1021/acs.jmedchem.5b00391

  日期：2015.7.23

  development. 5′-O-[N-(Salicyl)sulfamoyl]adenosine (1) is a bisubstrate inhibitor of MbtA and exhibits exceptionally potent biochemical and antitubercular activity. However, 1 suffers from suboptimal drug disposition properties resulting in a short half-life (t1/2), low exposure (AUC), and low bioavailability (F). Four strategies were pursued to address these liabilities including the synthesis of prodrugs

  MbtA催化分枝杆菌素的第一个重要的生物合成步骤，这是与结核分枝杆菌中铁摄入有关的重要毒力因子。MbtA是抗结核药物开发的经过验证的治疗靶标。5'- O- [ N-（水杨基）氨磺酰基]腺苷（1）是MbtA的双底物抑制剂，具有极强的生化和抗结核活性。然而，1的药物处置特性欠佳，导致半衰期短（t 1/2），低暴露（AUC）和低生物利用度（F）。采取了四种策略来解决这些问题，包括前药的合成，增加酰基磺酰基部分的p K a，调节亲脂性以及将氟引入1的策略。对所有化合物进行了完整的药代动力学（PK）分析。最成功的修饰涉及核苷的氟化，这可显着改善t 1/2和AUC。增加酰基-磺酰基接头的p K a会产生增量的增强，而亲脂性和前药方法的调节则导致PK参数大大降低。