| 181484-89-9

• 分子结构分类: 有机化合物 - 苯类化合物 - 三苯基化合物
• CAS: 181484-89-9
• 化学式: C₃₂H₃₅N₃O₅
• 分子量: 541.647
• InChiKey: NCBHASXBKFMODZ-NDEPHWFRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.34
• 重原子数：
  40.0
• 可旋转键数：
  9.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.28
• 拓扑面积：
  91.68
• 氢给体数：
  1.0
• 氢受体数：
  7.0

反应信息

• 作为反应物：
  描述：

  在 盐酸 、 氢氧化钾 、 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran 、 三乙胺 、 N,N'-羰基二咪唑 、 三氟乙酸 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 反应 24.0h， 生成 (S)-3-amino-4-(1H-imidazol-4-yl)-1-phenylbutan-2-one dihydrochloride
  参考文献：
  名称：

  Synthesis of potent inhibitors of histidinol dehydrogenase

  摘要：

  Novel inhibitors of histidinol dehydrogenase are described. The most potent inhibitors, compounds 18 (K-i* = 4.4 nM) and 19 (K-i* = 2.9 nM) exploit a hitherto unreported lipophilic binding pocket adjoining the active site. Preliminary SAR data for this pocket are detailed. The electrophilic ketone 6 designed to bind to an active site nucleophile was a considerably weaker inhibitor (IC50 similar to 20 mu M). Copyright (C) 1996 Elsevier Science Ltd

  DOI：

  10.1016/0960-894x(96)00384-8
• 作为产物：
  描述：

  L-组氨酸甲酯 在 potassium carbonate 、 三乙胺 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 48.0h， 生成
  参考文献：
  名称：

  Synthesis of potent inhibitors of histidinol dehydrogenase

  摘要：

  Novel inhibitors of histidinol dehydrogenase are described. The most potent inhibitors, compounds 18 (K-i* = 4.4 nM) and 19 (K-i* = 2.9 nM) exploit a hitherto unreported lipophilic binding pocket adjoining the active site. Preliminary SAR data for this pocket are detailed. The electrophilic ketone 6 designed to bind to an active site nucleophile was a considerably weaker inhibitor (IC50 similar to 20 mu M). Copyright (C) 1996 Elsevier Science Ltd

  DOI：

  10.1016/0960-894x(96)00384-8

文献信息

• Anti-virulence Strategy against Brucella suis: Synthesis, Biological Evaluation and Molecular Modeling of Selective Histidinol Dehydrogenase Inhibitors
  作者：Marie-Rose Abdo、Pascale Joseph、Jérémie Mortier、François Turtaut、Jean-Louis Montero、Bernard Masereel、Stephan Köhler、Jean-Yves Winum

  DOI：10.1039/c1ob05149k

  日期：——

  In the facultative intracellular pathogen Brucella suis, histidinol dehydrogenase (HDH) activity, catalyzing the last step in histidine biosynthesis, is essential for intramacrophagic replication. The inhibition of this virulence factor by substituted benzylic ketones was a proof of concept that disarming bacteria leads to inhibition of intracellular bacterial growth in macrophage infection. This work describes the design, synthesis and evaluation of 19 new potential HDH inhibitors, using a combination of classical approaches and docking studies. The IC50-values of these inhibitors on HDH activity were in the nanomolar range, and several of them showed a 70–100% inhibition of Brucellagrowth in minimal medium. One selected compound yielded a strong inhibitory effect on intracellular replication of B. suis in human macrophages at concentrations as low as 5 μM, with an overall survival of intramacrophagic bacteria reduced by a factor 103. Docking studies with two inhibitors showed a good fitting in the catalytic pocket and also interaction with the second lipophilic pocket binding the cofactor NAD+. Experimental data confirmed competition between inhibitors and NAD+ at this site. Hence, these inhibitors can be considered as promising tools in the development of novel anti-virulence drugs.

  在选择性胞内病原体布鲁氏菌（Brucella suis）中，组氨酸醇脱氢酶（HDH）的活性对组氨酸生物合成的最后一步至关重要，并且对巨噬细胞内复制至关重要。用取代苄基酮抑制这一毒力因子证明，解除细菌武装可以抑制巨噬细胞感染中的胞内细菌生长。本研究描述了使用经典方法与对接研究相结合，设计、合成和评估19种新潜在的HDH抑制剂。这些抑制剂对HDH活性的IC50值在纳摩尔范围内，其中几种在最小培养基中对布鲁氏菌的生长显示出70%至100%的抑制效果。选定的一个化合物在低至5μM的浓度下对人类巨噬细胞中B. suis的胞内复制产生了强抑制作用，使巨噬细胞内细菌的存活率降低了103倍。对接研究表明，两种抑制剂在催化口袋中匹配良好，并且与结合辅因子NAD+的第二个脂亲和口袋也有相互作用。实验数据证实了抑制剂与NAD+在该位点之间的竞争。因此，这些抑制剂可以被视为开发新型抗毒力药物的有前景的工具。