2-(2-{[5-(2,6-dichlorophenyl)[1,2,4]triazin-3-ylamino]methyl}benzothiazol-5-yloxy)ethanol | 1203603-92-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并噻唑类
• 英文名称: 2-(2-{[5-(2,6-dichlorophenyl)[1,2,4]triazin-3-ylamino]methyl}benzothiazol-5-yloxy)ethanol
• 英文别名: 2-{[2-({[5-(2,6-dichlorophenyl)-1,2,4-triazin-3-yl]amino}methyl)-1,3-benzothiazol-5-yl]oxy}ethanol；2-[[2-[[[5-(2,6-Dichlorophenyl)-1,2,4-triazin-3-yl]amino]methyl]-1,3-benzothiazol-5-yl]oxy]ethanol
• CAS: 1203603-92-2
• 化学式: C₁₉H₁₅Cl₂N₅O₂S
• 分子量: 448.332
• InChiKey: BJNBXXVGCQPKSA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  29
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.16
• 拓扑面积：
  121
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  2-(2-{[5-(2,6-dichlorophenyl)[1,2,4]triazin-3-ylamino]methyl}benzothiazol-5-yloxy)ethanol 在 三乙胺 作用下， 以 四氢呋喃 、 乙腈 为溶剂， 反应 50.5h， 生成 5-(2,6-dichlorophenyl)-N-[[5-[2-(4-methylpiperazin-1-yl)ethoxy]-1,3-benzothiazol-2-yl]methyl]-1,2,4-triazin-3-amine
  参考文献：
  名称：

  Vectorization Efforts To Increase Gram-Negative Intracellular Drug Concentration: A Case Study on HldE-K Inhibitors

  摘要：

  In this paper, we present different strategies to vectorize HldE kinase inhibitors with the goal to improve their Gram-negative intracellular concentration. Syntheses and biological effects of siderophoric, aminoglycosidic, amphoteric, and polycationic vectors are discussed. While siderophoric and amphoteric vectorization efforts proved to be disappointing in this series, aminoglycosidic and polycationic vectors were able for the first time to achieve synergistic effects of our inhibitors with erythromycin. Although these effects proved to be nonspecific, this study provides information about the required stereoelectronic arrangement of the polycationic amines and their basicity requirements to fulfill outer membrane destabilization resulting in better erythromycin synergies.

  DOI：

  10.1021/jm400097h
• 作为产物：
  描述：

  2',6'-二氯苯乙酮 在 selenium(IV) oxide 、 sodium tetrahydroborate 、 三溴化硼 、 二异丁基氢化铝 、 potassium carbonate 、 N,N-二异丙基乙胺 、 三氯氧磷 作用下， 以 1,4-二氧六环 、 甲醇 、 乙醇 、 二氯甲烷 、 氯仿 、 水 、 N,N-二甲基甲酰胺 、 丙酮 、 甲苯 、 乙腈 为溶剂， 反应 23.5h， 生成 2-(2-{[5-(2,6-dichlorophenyl)[1,2,4]triazin-3-ylamino]methyl}benzothiazol-5-yloxy)ethanol
  参考文献：
  名称：

  Novel HldE-K Inhibitors Leading to Attenuated Gram Negative Bacterial Virulence

  摘要：

  We report here the optimization of an HldE kinase inhibitor to low nanomolar potency, which resulted in the identification of the first reported compounds active on selected E. coli strains. One of the most interesting candidates, compound 86, was shown to inhibit specifically bacterial I,PS heptosylation on efflux pump deleted E. coli strains. This compound did not interfere with E. coli bacterial growth (MIC > 32 mu g/mL) but sensitized this pathogen to hydrophobic antibiotics like macrolides normally inactive on Gram-negative bacteria. In addition, 86 could sensitize E. coli to serum complement killing. These results demonstrate that HldE kinase is a suitable target for drug discovery. They also pave the way toward novel possibilities of treating or preventing bloodstream infections caused by pathogenic Gram negative bacteria by inhibiting specific virulence factors.

  DOI：

  10.1021/jm301499r

文献信息

• New 1,2,4-triazine derivatives and biological applications thereof
  申请人：Mutabilis

  公开号：EP2141164A1

  公开（公告）日：2010-01-06

  The invention relates to new 1,2,4-triazine derivatives of formula (I): wherein A, B, R2 and Y are defined in the application, their preparation and intermediates, their use as drugs and pharmaceutical compositions and associations containing them. The compounds of formula (I) are capable of inhibiting bacterial heptose synthesis.

  这项发明涉及公式(I)的新1,2,4-三嗪衍生物： 其中A、B、R2和Y在申请中有定义， 它们的制备和中间体，它们作为药物和药物组合物的用途以及含有它们的关联物。 公式(I)的化合物能够抑制细菌七糖合成。
• [EN] NEW 1,2,4-TRIAZINE DERIVATIVES AND BIOLOGICAL APPLICATIONS THEREOF<br/>[FR] NOUVEAUX DÉRIVÉS DE 1,2,4-TRIAZINE ET LEURS APPLICATIONS BIOLOGIQUES
  申请人：MUTABILIS SA

  公开号：WO2010001220A1

  公开（公告）日：2010-01-07

  The invention relates to new 1,2,4-triazine derivatives of formula (I): wherein A, B, R2 and Y are defined in the application, their preparation and intermediates, their use as drugs and pharmaceutical compositions and associations containing them. The compounds of formula (I) are capable of inhibiting bacterial heptose synthesis.
• Vectorization Efforts To Increase Gram-Negative Intracellular Drug Concentration: A Case Study on HldE-K Inhibitors
  作者：Dmytro Atamanyuk、Fabien Faivre、Mayalen Oxoby、Benoit Ledoussal、Elodie Drocourt、François Moreau、Vincent Gerusz

  DOI：10.1021/jm400097h

  日期：2013.3.14

  In this paper, we present different strategies to vectorize HldE kinase inhibitors with the goal to improve their Gram-negative intracellular concentration. Syntheses and biological effects of siderophoric, aminoglycosidic, amphoteric, and polycationic vectors are discussed. While siderophoric and amphoteric vectorization efforts proved to be disappointing in this series, aminoglycosidic and polycationic vectors were able for the first time to achieve synergistic effects of our inhibitors with erythromycin. Although these effects proved to be nonspecific, this study provides information about the required stereoelectronic arrangement of the polycationic amines and their basicity requirements to fulfill outer membrane destabilization resulting in better erythromycin synergies.
• Novel HldE-K Inhibitors Leading to Attenuated Gram Negative Bacterial Virulence
  作者：Nicolas Desroy、Alexis Denis、Chrystelle Oliveira、Dmytro Atamanyuk、Sophia Briet、Fabien Faivre、Géraldine LeFralliec、Yannick Bonvin、Mayalen Oxoby、Sonia Escaich、Stéphanie Floquet、Elodie Drocourt、Vanida Vongsouthi、Lionel Durant、François Moreau、Theodore B. Verhey、Ting-Wai Lee、Murray S. Junop、Vincent Gerusz

  DOI：10.1021/jm301499r

  日期：2013.2.28

  We report here the optimization of an HldE kinase inhibitor to low nanomolar potency, which resulted in the identification of the first reported compounds active on selected E. coli strains. One of the most interesting candidates, compound 86, was shown to inhibit specifically bacterial I,PS heptosylation on efflux pump deleted E. coli strains. This compound did not interfere with E. coli bacterial growth (MIC > 32 mu g/mL) but sensitized this pathogen to hydrophobic antibiotics like macrolides normally inactive on Gram-negative bacteria. In addition, 86 could sensitize E. coli to serum complement killing. These results demonstrate that HldE kinase is a suitable target for drug discovery. They also pave the way toward novel possibilities of treating or preventing bloodstream infections caused by pathogenic Gram negative bacteria by inhibiting specific virulence factors.