tert-butyl (2-(hydroxyamino)-2-oxo-1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)ethyl)carbamate

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: tert-butyl (2-(hydroxyamino)-2-oxo-1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)ethyl)carbamate
• 英文别名: tert-butyl N-[2-(hydroxyamino)-2-oxo-1-[4-[4-(trifluoromethyl)phenyl]phenyl]ethyl]carbamate
• 化学式: C₂₀H₂₁F₃N₂O₄
• 分子量: 410.393
• InChiKey: BPCYQZNZZAQLNP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  29
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  87.7
• 氢给体数：
  3
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  Dl-4-溴苯甘氨酸 在 bis-triphenylphosphine-palladium(II) chloride 、 盐酸羟胺 、 sodium carbonate 、 potassium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 水 为溶剂， 反应 2.0h， 生成 tert-butyl (2-(hydroxyamino)-2-oxo-1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)ethyl)carbamate
  参考文献：
  名称：

  Potent dual inhibitors of Plasmodium falciparum M1 and M17 aminopeptidases through optimization of S1 pocket interactions

  摘要：

  Malaria remains a global health problem, and though international efforts for treatment and eradication have made some headway, the emergence of drug-resistant parasites threatens this progress. Antimalarial therapeutics acting via novel mechanisms are urgently required. Plasmodium falciparum M1 and M17 are neutral aminopeptidases which are essential for parasite growth and development. Previous work in our group has identified inhibitors capable of dual inhibition of PfA-M1 and PfA-M17, and revealed further regions within the protease S1 pockets that could be exploited in the development of ligands with improved inhibitory activity. Herein, we report the structure-based design and synthesis of novel hydroxamic acid analogues that are capable of potent inhibition of both PfA-M1 and PfA-M17. Furthermore, the developed compounds potently inhibit Pf growth in culture, including the multi-drug resistant strain Dd2. The ongoing development of dual PIA-M1/PfA-M17 inhibitors continues to be an attractive strategy for the design of novel antimalarial therapeutics. (C) 2016 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2016.01.015

文献信息

• [EN] NOVEL AMINOPEPTIDASE INHIBITORS AND METHODS OF USE<br/>[FR] NOUVEAUX INHIBITEURS D'AMINOPEPTIDASE ET PROCÉDÉS D'UTILISATION
  申请人：UNIV MONASH

  公开号：WO2017008101A1

  公开（公告）日：2017-01-19

  An aminopeptidase inhibitor compound comprising a biaryl, hydroxamic acid based core of formula: wherein X is a 5 or 6-membered ring, and including pharmaceutically acceptable salts and solvates thereof.

  一种含有生物芳基、羟肟酸基核的氨基肽酶抑制剂化合物，其化学式为：其中X为5或6元环，并包括其药用可接受的盐和溶剂化合物。
• Potent dual inhibitors of Plasmodium falciparum M1 and M17 aminopeptidases through optimization of S1 pocket interactions
  作者：Nyssa Drinkwater、Natalie B. Vinh、Shailesh N. Mistry、Rebecca S. Bamert、Chiara Ruggeri、John P. Holleran、Sasdekumar Loganathan、Alessandro Paiardini、Susan A. Charman、Andrew K. Powell、Vicky M. Avery、Sheena McGowan、Peter J. Scammells

  DOI：10.1016/j.ejmech.2016.01.015

  日期：2016.3

  Malaria remains a global health problem, and though international efforts for treatment and eradication have made some headway, the emergence of drug-resistant parasites threatens this progress. Antimalarial therapeutics acting via novel mechanisms are urgently required. Plasmodium falciparum M1 and M17 are neutral aminopeptidases which are essential for parasite growth and development. Previous work in our group has identified inhibitors capable of dual inhibition of PfA-M1 and PfA-M17, and revealed further regions within the protease S1 pockets that could be exploited in the development of ligands with improved inhibitory activity. Herein, we report the structure-based design and synthesis of novel hydroxamic acid analogues that are capable of potent inhibition of both PfA-M1 and PfA-M17. Furthermore, the developed compounds potently inhibit Pf growth in culture, including the multi-drug resistant strain Dd2. The ongoing development of dual PIA-M1/PfA-M17 inhibitors continues to be an attractive strategy for the design of novel antimalarial therapeutics. (C) 2016 Elsevier Masson SAS. All rights reserved.