2-amino-8-((1-oxo-1-phenylpropan-2-yl)thio)-1,9-dihydro-6H-purin-6-one

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 2-amino-8-((1-oxo-1-phenylpropan-2-yl)thio)-1,9-dihydro-6H-purin-6-one
• 英文别名: 2-Amino-8-(1-oxo-1-phenylpropan-2-yl)sulfanyl-1,7-dihydropurin-6-one；2-amino-8-(1-oxo-1-phenylpropan-2-yl)sulfanyl-1,7-dihydropurin-6-one
• 化学式: C₁₄H₁₃N₅O₂S
• 分子量: 315.356
• InChiKey: WMRNTHKIMJOGCD-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  22
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.14
• 拓扑面积：
  139
• 氢给体数：
  3
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  2-溴苯丙酮 、 8-mercaptoguanine 在 sodium hydroxide 作用下， 以 水 为溶剂， 反应 1.0h， 以30.8%的产率得到2-amino-8-((1-oxo-1-phenylpropan-2-yl)thio)-1,9-dihydro-6H-purin-6-one
  参考文献：
  名称：

  The identification, analysis and structure-based development of novel inhibitors of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase

  摘要：

  6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) is an essential enzyme in the microbial folate biosynthetic pathway. This pathway has proven to be an excellent target for antimicrobial development, but widespread resistance to common therapeutics including the sulfa drugs has stimulated interest in HPPK as an alternative target in the pathway. A screen of a pterin-biased compound set identified several HPPK inhibitors that contain an aryl substituted 8-thioguanine scaffold, and structural analyses showed that these compounds engage the HPPK pterin-binding pocket and an induced cryptic pocket. A preliminary structure activity relationship profile was developed from biophysical and biochemical characterizations of derivative molecules. Also, a similarity search identified additional scaffolds that bind more tightly within the HPPK pterin pocket. These inhibitory scaffolds have the potential for rapid elaboration into novel lead antimicrobial agents. (C) 2014 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2014.02.022

文献信息

• The identification, analysis and structure-based development of novel inhibitors of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase
  作者：Mi-Kyung Yun、Daniel Hoagland、Gyanendra Kumar、M. Brett Waddell、Charles O. Rock、Richard E. Lee、Stephen W. White

  DOI：10.1016/j.bmc.2014.02.022

  日期：2014.4

  6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) is an essential enzyme in the microbial folate biosynthetic pathway. This pathway has proven to be an excellent target for antimicrobial development, but widespread resistance to common therapeutics including the sulfa drugs has stimulated interest in HPPK as an alternative target in the pathway. A screen of a pterin-biased compound set identified several HPPK inhibitors that contain an aryl substituted 8-thioguanine scaffold, and structural analyses showed that these compounds engage the HPPK pterin-binding pocket and an induced cryptic pocket. A preliminary structure activity relationship profile was developed from biophysical and biochemical characterizations of derivative molecules. Also, a similarity search identified additional scaffolds that bind more tightly within the HPPK pterin pocket. These inhibitory scaffolds have the potential for rapid elaboration into novel lead antimicrobial agents. (C) 2014 Elsevier Ltd. All rights reserved.
• Structure-Based Design and Development of Functionalized Mercaptoguanine Derivatives as Inhibitors of the Folate Biosynthesis Pathway Enzyme 6-Hydroxymethyl-7,8-dihydropterin Pyrophosphokinase from <i>Staphylococcus aureus</i>
  作者：Matthew L. Dennis、Sandeep Chhabra、Zhong-Chang Wang、Aaron Debono、Olan Dolezal、Janet Newman、Noel P. Pitcher、Raphael Rahmani、Ben Cleary、Nicholas Barlow、Meghan Hattarki、Bim Graham、Thomas S. Peat、Jonathan B. Baell、James D. Swarbrick

  DOI：10.1021/jm501417f

  日期：2014.11.26

  6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK), an enzyme from the folate biosynthesis pathway, catalyzes the pyrophosphoryl transfer from ATP to 6-hydroxymethyl-7,8-dihydropterin and is a yet-to-be-drugged antimicrobial target. Building on our previous discovery that 8-mercaptoguanine (8MG) is an inhibitor of Staphylococcus aureus HPPK (SaHPPK), we have identified and characterized the binding of an S8-functionalized derivative (3). X-ray structures of both the SaHPPK/3/cofactor analogue ternary and the SaHPPK/cofactor analogue binary complexes have provided insight into cofactor recognition and key residues that move over 30 angstrom upon binding of 3, whereas NMR measurements reveal a partially plastic ternary complex active site. Synthesis and binding analysis of a set of analogues of 3 have identified an advanced new lead compound (11) displaying >20-fold higher affinity for SaHPPK than 8MG. A number of these exhibited low micromolar affinity for dihydropteroate synthase (DHPS), the adjacent, downstream enzyme to HPPK, and may thus represent promising new leads to bienzyme inhibitors.