2-((4,5-bis((4-methoxybenzyl)oxy)pyridin-2-yl)(thiazol-2-yl)methoxy)isoindoline-1,3-dione

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异吲哚及其衍生物
• 英文名称: 2-((4,5-bis((4-methoxybenzyl)oxy)pyridin-2-yl)(thiazol-2-yl)methoxy)isoindoline-1,3-dione
• 英文别名: 2-[[4,5-Bis[(4-methoxyphenyl)methoxy]pyridin-2-yl]-(1,3-thiazol-2-yl)methoxy]isoindole-1,3-dione；2-[[4,5-bis[(4-methoxyphenyl)methoxy]pyridin-2-yl]-(1,3-thiazol-2-yl)methoxy]isoindole-1,3-dione
• 化学式: C₃₃H₂₇N₃O₇S
• 分子量: 609.659
• InChiKey: AJFACZCIQODSGP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5
• 重原子数：
  44
• 可旋转键数：
  12
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.15
• 拓扑面积：
  138
• 氢给体数：
  0
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  2-((4,5-bis((4-methoxybenzyl)oxy)pyridin-2-yl)(thiazol-2-yl)methoxy)isoindoline-1,3-dione 在 hydrazine hydrate 、 间氯过氧苯甲酸 作用下， 以 二氯甲烷 为溶剂， 反应 4.33h， 生成 (Z)-2-((((carboxy(2-(tritylamino)thiazol-4-yl)methylene)amino)oxy)(thiazol-2-yl)methyl)-4,5-bis((4-methoxybenzyl)oxy)pyridine 1-oxide
  参考文献：
  名称：

  Discovery of Novel Pyridone-Conjugated Monosulfactams as Potent and Broad-Spectrum Antibiotics for Multidrug-Resistant Gram-Negative Infections

  摘要：

  Conjugating a siderophore to an antibiotic is a promising strategy to overcome the permeability-mediated resistance of Gram-negative pathogens. On the basis of the structure of BAL30072, novel pyridone-conjugated mono-sulfactams incorporating diverse substituents into the methylene linker between the 1,3-dihydroxypyridin-4(1H)-one and the aminothiazole oxime were designed and synthesized. Structure activity relationship studies revealed that a variety of substituents were tolerated, with isopropyl (compound 12c) and methylthiomethyl (compound 16a) showing the best efficacy against multidrug-resistant (MDR) Gram-negative pathogens. In addition, compound 12c exhibits a good free fraction rate in an in vitro human plasma protein binding test, along with a low clearance and favorable plasma exposure in vivo. In a murine systemic infection model with MDR Klebsiella pneumoniae, compound 12c shows an ED50 of 10.20 mg/kg. Taken together, the results indicate that compound 12c is a promising drug candidate for the treatment of serious infections caused by MDR Gram-negative pathogens.

  DOI：

  10.1021/acs.jmedchem.6b01261
• 作为产物：
  描述：

  2-(羟甲基)-5-[(4-甲氧基苯基)甲氧基]-1H-吡啶-4-酮 在 正丁基锂 、 三氧化硫吡啶 、 potassium carbonate 、 三乙胺 、 三苯基膦 、 偶氮二甲酸二乙酯 作用下， 以 四氢呋喃 、 正己烷 、 二氯甲烷 、 二甲基亚砜 为溶剂， 反应 7.5h， 生成 2-((4,5-bis((4-methoxybenzyl)oxy)pyridin-2-yl)(thiazol-2-yl)methoxy)isoindoline-1,3-dione
  参考文献：
  名称：

  Discovery of Novel Pyridone-Conjugated Monosulfactams as Potent and Broad-Spectrum Antibiotics for Multidrug-Resistant Gram-Negative Infections

  摘要：

  Conjugating a siderophore to an antibiotic is a promising strategy to overcome the permeability-mediated resistance of Gram-negative pathogens. On the basis of the structure of BAL30072, novel pyridone-conjugated mono-sulfactams incorporating diverse substituents into the methylene linker between the 1,3-dihydroxypyridin-4(1H)-one and the aminothiazole oxime were designed and synthesized. Structure activity relationship studies revealed that a variety of substituents were tolerated, with isopropyl (compound 12c) and methylthiomethyl (compound 16a) showing the best efficacy against multidrug-resistant (MDR) Gram-negative pathogens. In addition, compound 12c exhibits a good free fraction rate in an in vitro human plasma protein binding test, along with a low clearance and favorable plasma exposure in vivo. In a murine systemic infection model with MDR Klebsiella pneumoniae, compound 12c shows an ED50 of 10.20 mg/kg. Taken together, the results indicate that compound 12c is a promising drug candidate for the treatment of serious infections caused by MDR Gram-negative pathogens.

  DOI：

  10.1021/acs.jmedchem.6b01261

文献信息

• [EN] MONOCYCLIC Β-LACTAM-IRON CARRIER CONJUGATE, AND MANUFACTURING METHOD AND APPLICATION THEREOF<br/>[FR] CONJUGUÉ DE SUPPORT DE BÊTA-LACTAME-FER MONOCYCLIQUE, PROCÉDÉ DE PRODUCTION ET APPLICATION ASSOCIÉE<br/>[ZH] 单环β-内酰胺-铁载体轭合物及其制备方法和用途
  申请人：SHANGHAI INST MATERIA MEDICA CAS

  公开号：WO2018014823A1

  公开（公告）日：2018-01-25

  提供如下通式(I)所示的单环β-内酰胺-铁载体轭合物，其光学异构体或其药学上可接受的盐，以及其合成方法和其在治疗细菌感染性疾病中的用途。
• MONOCYCLIC B-LACTAM-IRON CARRIER CONJUGATE, AND MANUFACTURING METHOD AND APPLICATION THEREOF
  申请人：Shanghai Institute of Materia Medica, Chinese Academy of Sciences

  公开号：EP3489234B1

  公开（公告）日：2020-03-18
• Discovery of Novel Pyridone-Conjugated Monosulfactams as Potent and Broad-Spectrum Antibiotics for Multidrug-Resistant Gram-Negative Infections
  作者：Liang Tan、Yunliang Tao、Ting Wang、Feng Zou、Shuhua Zhang、Qunhuan Kou、Ao Niu、Qian Chen、Wenjing Chu、Xiaoyan Chen、Haidong Wang、Yushe Yang

  DOI：10.1021/acs.jmedchem.6b01261

  日期：2017.4.13

  Conjugating a siderophore to an antibiotic is a promising strategy to overcome the permeability-mediated resistance of Gram-negative pathogens. On the basis of the structure of BAL30072, novel pyridone-conjugated mono-sulfactams incorporating diverse substituents into the methylene linker between the 1,3-dihydroxypyridin-4(1H)-one and the aminothiazole oxime were designed and synthesized. Structure activity relationship studies revealed that a variety of substituents were tolerated, with isopropyl (compound 12c) and methylthiomethyl (compound 16a) showing the best efficacy against multidrug-resistant (MDR) Gram-negative pathogens. In addition, compound 12c exhibits a good free fraction rate in an in vitro human plasma protein binding test, along with a low clearance and favorable plasma exposure in vivo. In a murine systemic infection model with MDR Klebsiella pneumoniae, compound 12c shows an ED50 of 10.20 mg/kg. Taken together, the results indicate that compound 12c is a promising drug candidate for the treatment of serious infections caused by MDR Gram-negative pathogens.