5-[4,5-双(苯甲氧基)-2-吡啶基]-1,3,4-恶二唑-2(3H)-酮 | 1229937-09-0

• 分子结构分类: 有机化合物 - 有机氧化合物
• 中文名称: 5-[4,5-双(苯甲氧基)-2-吡啶基]-1,3,4-恶二唑-2(3H)-酮
• 英文名称: 5-(4,5-bis(benzyloxy)pyridin-2-yl)-1,3,4-oxadiazol-2(3H)-one
• 英文别名: 5-(4,5-bis(benzyloxy)pyridin-2-yl)-1,3,4-oxadiazol-2(5H)-one；5-[4,5-bis(phenylmethoxy)pyridin-2-yl]-3H-1,3,4-oxadiazol-2-one
• CAS: 1229937-09-0
• 化学式: C₂₁H₁₇N₃O₄
• 分子量: 375.384
• InChiKey: SEROJOMPCMRBRI-UHFFFAOYSA-N

物化性质

• 密度：
  1.30

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  28
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.1
• 拓扑面积：
  82
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  5-[4,5-双(苯甲氧基)-2-吡啶基]-1,3,4-恶二唑-2(3H)-酮 在 氢气 、 钯 、 三乙胺 、 间氯过氧苯甲酸 、 三氟乙酸 、 potassium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 水 为溶剂， 100.0 ℃ 、101.33 kPa 条件下， 反应 13.5h， 生成 2-(((Z)-(1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-(((3-(5-hydroxy-4-oxo-1,4-dihydropyridin-2-yl)-4-(4-(methylsulfonyl)butyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)sulfonyl)carbamoyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoic acid
  参考文献：
  名称：

  SAR and Structural Analysis of Siderophore-Conjugated Monocarbam Inhibitors of Pseudomonas aeruginosa PBP3

  摘要：

  A main challenge in the development of new agents for the treatment of Pseudomonas aeruginosa infections is the identification of chemotypes that efficiently penetrate the cell envelope and are not susceptible to established resistance mechanisms. Siderophore-conjugated monocarbams are attractive because of their ability to hijack the bacteria's iron uptake machinery for transport into the periplasm and their inherent stability to metallo-beta-lactamases. Through development of the SAR we identified a number of modifications to the scaffold that afforded active anti-P. aeruginosa agents with good physicochemical properties. Through crystallographic efforts we gained a better understanding into how these compounds bind to the target penicillin binding protein PBP3 and factors to consider for future design.

  DOI：

  10.1021/acsmedchemlett.5b00026
• 作为产物：
  描述：

  4,5-二苄氧基吡啶甲酸苄酯 在 一水合肼 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 生成 5-[4,5-双(苯甲氧基)-2-吡啶基]-1,3,4-恶二唑-2(3H)-酮
  参考文献：
  名称：

  Preparation, Gram-Negative Antibacterial Activity, and Hydrolytic Stability of Novel Siderophore-Conjugated Monocarbam Diols

  摘要：

  A novel series of monocarbam compounds exhibiting promising antibacterial activity against multidrug resistant Gram-negative microorganisms is reported, along with the synthesis of one such molecule MC-1 (1). Also reported are structure-activity relationships associated with the in vitro and in vivo efficacy of 1 and related analogues in addition to the hydrolytic stability of such compounds and possible implications thereof.

  DOI：

  10.1021/ml200012f

文献信息

• MONOCARBAMS
  申请人：Brickner Steven Joseph

  公开号：US20100160281A1

  公开（公告）日：2010-06-24

  The invention relates to compounds of formula (I): wherein R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 as defined herein. The invention also relates to pharmaceutical compositions and methods of treating bacterial infections using compounds of formula (I).

  这项发明涉及式(I)的化合物： 其中R1，R2，R3，R4，R5和R6如本文所定义。该发明还涉及使用式(I)的化合物治疗细菌感染的药物组合物和方法。
• Pharmacodynamic Profiling of a Siderophore-Conjugated Monocarbam in Pseudomonas aeruginosa: Assessing the Risk for Resistance and Attenuated Efficacy
  作者：Aryun Kim、Amy Kutschke、David E. Ehmann、Sara A. Patey、Jared L. Crandon、Elise Gorseth、Alita A. Miller、Robert E. McLaughlin、Christina M. Blinn、April Chen、Asha S. Nayar、Brian Dangel、Andy S. Tsai、Michael T. Rooney、Kerry E. Murphy-Benenato、Ann E. Eakin、David P. Nicolau

  DOI：10.1128/aac.00831-15

  日期：2015.12

  The objective of this study was to investigate the risk of attenuated efficacy due to adaptive resistance for the siderophore-conjugated monocarbam SMC-3176 in Pseudomonas aeruginosa by using a pharmacokinetic/pharmacodynamic (PK/PD) approach. MICs were determined in cation-adjusted Mueller-Hinton broth (MHB) and in Chelex-treated, dialyzed MHB (CDMHB). Spontaneous resistance was assessed at 2× to 16× the MIC and the resulting mutants sequenced. Efficacy was evaluated in a neutropenic mouse thigh model at 3.13 to 400 mg/kg of body weight every 3 h for 24 h and analyzed for association with free time above the MIC ( fT >MIC). To closer emulate the conditions of the in vivo model, we developed a novel assay testing activity mouse whole blood (WB). All mutations were found in genes related to iron uptake: piuA , piuC , pirR , fecI , and pvdS . Against four P. aeruginosa isolates, SMC-3176 displayed predictable efficacy corresponding to the fT >MIC using the MIC in CDMHB ( R ² = 0.968 to 0.985), with stasis to 2-log kill achieved at 59.4 to 81.1%. Efficacy did not translate for P. aeruginosa isolate JJ 4-36, as the in vivo responses were inconsistent with fT >MIC exposures and implied a threshold concentration that was greater than the MIC. The results of the mouse WB assay indicated that efficacy was not predictable using the MIC for JJ 4-36 and four additional isolates, against which in vivo failures of another siderophore-conjugated β-lactam were previously reported. SMC-3176 carries a risk of attenuated efficacy in P. aeruginosa due to rapid adaptive resistance preventing entry via the siderophore-mediated iron uptake systems. Substantial in vivo testing is warranted for compounds using the siderophore approach to thoroughly screen for this in vitro-in vivo disconnect in P. aeruginosa .

  摘要 本研究的目的是调查苷元结合单卡巴姆 SMC-3176 在铜绿假单胞菌中的适应性抗药性导致药效减弱的风险。 铜绿假单胞菌 采用药代动力学/药效学（PK/PD）方法。在阳离子调整的穆勒-希顿肉汤（MHB）和经 Chelex 处理的透析 MHB（CDMHB）中测定了 MIC。在 MIC 为 2 倍至 16 倍时对自发耐药性进行评估，并对由此产生的突变体进行测序。在嗜中性粒细胞病小鼠大腿模型中，以每公斤体重 3.13 至 400 毫克的剂量，每 3 小时注射一次，连续注射 24 小时，对药效进行了评估，并分析了药效与高于 MIC 的自由时间（fT）的关系。 fT MIC）的相关性进行分析。为了更接近 体内 模型的条件，我们开发了一种检测小鼠全血（WB）活性的新型检测方法。所有突变都发生在与铁吸收有关的基因中： piuA , piuC , pirR , fecI 和 pvdS .针对四种 铜绿假单胞菌 分离物，SMC-3176 显示出与 fT >MIC（使用 CDMHB 中的 MIC ( R 2 = 0.968 到 0.985），59.4% 到 81.1%的杀灭率达到 2-log。对于 绿脓杆菌 分离物 JJ 4-36 的疗效没有转化为 体内 反应与 fT >MIC 暴露不一致，这意味着阈值浓度高于 MIC。小鼠 WB 检测结果表明，使用 JJ 4-36 和另外四种分离物的 MIC 无法预测药效。 体内 此前曾有报道称，另一种苷元结合的 β-内酰胺类药物对这四种分离物的体内疗效不佳。SMC-3176 对铜绿假单胞菌的疗效可能会减弱。 铜绿假单胞菌 SMC-3176 在铜绿假单胞菌中的疗效可能会减弱，因为快速的适应性抗药性会阻止其通过嗜苷铁元素介导的铁吸收系统进入体内。在 体内 测试，以彻底筛查这种 "体外-体内 "试验。 体外-体内 铜绿假单胞菌 铜绿假单胞菌 .
• [EN] MONOCARBAMS<br/>[FR] MONOCARBAMES
  申请人：PFIZER

  公开号：WO2010070523A1

  公开（公告）日：2010-06-24

  The invention relates to compounds of formula (I); wherein R1 R2, R3, R4, R5, and R6 as defined herein. The invention also relates to pharmaceutical compositions and methods of treating bacterial infections using compounds of formula (I),

  本发明涉及公式（I）的化合物；其中R1，R2，R3，R4，R5和R6如本文所定义。本发明还涉及使用公式（I）的化合物的制药组合物和治疗细菌感染的方法。
• Monocarbams
  申请人：Brickner Steven Joseph

  公开号：US20120289455A1

  公开（公告）日：2012-11-15

  The invention relates to compounds of formula (I): wherein R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 as defined herein. The invention also relates to pharmaceutical compositions and methods of treating bacterial infections using compounds of formula (I).
• US8252782B2
  申请人：——

  公开号：US8252782B2

  公开（公告）日：2012-08-28