(1R)-2-(4-carboxy[1,2,3]triazol-1-yl)-1-[(2-thienylacetyl)amino]ethaneboronic acid | 1429666-61-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: (1R)-2-(4-carboxy[1,2,3]triazol-1-yl)-1-[(2-thienylacetyl)amino]ethaneboronic acid
• 英文别名: S02030；1-[(2R)-2-borono-2-[(2-thiophen-2-ylacetyl)amino]ethyl]triazole-4-carboxylic acid
• CAS: 1429666-61-4
• 化学式: C₁₁H₁₃BN₄O₅S
• 分子量: 324.125
• InChiKey: ZXGRTNOGXAKRBS-VIFPVBQESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -1.22
• 重原子数：
  22
• 可旋转键数：
  7
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  166
• 氢给体数：
  4
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  (+)-pinanediol (1R)-2-azido-1-[(2-thienylacetyl)amino]ethaneboronate 在 盐酸 、 copper in charcoal 、 苯硼酸 作用下， 以 1,4-二氧六环 、 正己烷 、 水 、 乙腈 为溶剂， 反应 3.5h， 生成 (1R)-2-(4-carboxy[1,2,3]triazol-1-yl)-1-[(2-thienylacetyl)amino]ethaneboronic acid
  参考文献：
  名称：

  Biochemical and Structural Analysis of Inhibitors Targeting the ADC-7 Cephalosporinase of Acinetobacter baumannii

  摘要：

  beta-Lactam resistance in Acinetobacter baumannii presents one of the greatest challenges to contemporary antimicrobial chemotherapy. Much of this resistance to cephalosporins derives from the expression of the class C beta-lactamase enzymes, known as Acinetobacter-derived cephalosporinases (ADCs). Currently, beta-lactamase inhibitors are structurally similar to beta-lactam substrates and are not effective inactivators of this class C cephalosporinase. Herein, two boronic acid transition state inhibitors (BATSIs S02030 and SM23) that are chemically distinct from beta-lactams were designed and tested for inhibition of ADC enzymes. BATSIs SM23 and S02030 bind with high affinity to ADC-7, a chromosomal cephalosporinase from Acinetobacter baumannii (K-i = 21.1 +/- 1.9 nM and 44.5 +/- 2.2 nM, respectively). The X-ray crystal structures of ADC-7 were determined in both the apo form (1.73 angstrom resolution) and in complex with S02030 (2.0 angstrom resolution). In the complex, S02030 makes several canonical interactions: the O1 oxygen of S02030 is bound in the oxyanion hole, and the R1 amide group makes key interactions with conserved residues Asn152 and Gln120. In addition, the carboxylate group of the inhibitor is meant to mimic the C-3/C-4 carboxylate found in beta-lactams. The C-3/C-4 carboxylate recognition site in class C enzymes is comprised of Asn346 and Arg349 (AmpC numbering), and these residues are conserved in ADC-7. Interestingly, in the ADC-7/S02030 complex, the inhibitor carboxylate group is observed to interact with Arg340, a residue that distinguishes ADC-7 from the related class C enzyme AmpC. A thermodynamic analysis suggests that Delta H driven compounds may be optimized to generate new lead agents. The ADC-7/BATSI complex provides insight into recognition of non-beta-lactam inhibitors by ADC enzymes and offers a starting point for the structure-based optimization of this class of novel beta-lactamase inhibitors against a key resistance target.

  DOI：

  10.1021/bi500887n

文献信息

• BORONIC ACID DERIVATIVES AND THERAPEUTIC USES THEREOF
  申请人：Rempex Pharmaceuticals, Inc.

  公开号：US20130316978A1

  公开（公告）日：2013-11-28

  Disclosed herein are antimicrobial compounds compositions, pharmaceutical compositions, the use and preparation thereof. Some embodiments relate to boronic acid derivatives and their use as therapeutic agents.

  本文披露了抗菌化合物组合物、药物组合物的成分、使用和制备方法。一些实施例涉及硼酸衍生物及其作为治疗剂的使用。
• Click Chemistry in Lead Optimization of Boronic Acids as β-Lactamase Inhibitors
  作者：Emilia Caselli、Chiara Romagnoli、Roza Vahabi、Magdalena A. Taracila、Robert A. Bonomo、Fabio Prati

  DOI：10.1021/acs.jmedchem.5b00341

  日期：2015.7.23

  Boronic acid transition-state inhibitors (BAT-SIs) represent one of the most promising classes of beta-lactamase inhibitors. Here we describe a new class of BATSIs, namely, 1-amido-2-triazolylethaneboronic acids, which were synthesized by combining the asymmetric homologation of boronates with copper-catalyzed azide-alkyne cycloaddition for the stereoselective insertion of the amido group and the regioselective formation of the 1,4-disubstituted triazole, respectively. This synthetic pathway, which avoids intermediate purifications, proved to be flexible and efficient, affording in good yields a panel of 14 BATSIs bearing three different R1 amide side chains (acetamido, benzylamido, and 2-thienylacetamido) and Several R substituents on the triazole. This small library was tested against two clinically relevant class C beta-lactamases from Enterobacter spp. and Pseudomonas aeruginosa. The K-i value of the best compound (13a) was as low as 4 nM with significant reduction of bacterial resistance to the combination of cefotaxime/13a.