(+)-pinanediol (1R)-2-azido-1-[N,N-bis(trimethylsilyl)amino]ethaneboronate | 1425968-43-9

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 异戊烯醇脂质
• 英文名称: (+)-pinanediol (1R)-2-azido-1-[N,N-bis(trimethylsilyl)amino]ethaneboronate
• 英文别名: (+)-pinanediol 1S-bis-trimethylsilylamino-2-azidoethaneboronate
• CAS: 1425968-43-9
• 化学式: C₁₈H₃₇BN₄O₂Si₂
• 分子量: 408.499
• InChiKey: PWCLTKUANMSZHV-RPUYLAQPSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.9
• 重原子数：
  27.0
• 可旋转键数：
  6.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  1.0
• 拓扑面积：
  70.46
• 氢给体数：
  0.0
• 氢受体数：
  4.0

反应信息

• 作为反应物：
  描述：

  (+)-pinanediol (1R)-2-azido-1-[N,N-bis(trimethylsilyl)amino]ethaneboronate 在 甲醇 作用下， 以 四氢呋喃 为溶剂， 反应 1.17h， 生成 (+)-pinanediol (1R)-2-azido-1-[(2-thienylacetyl)amino]ethaneboronate
  参考文献：
  名称：

  Click Chemistry in Lead Optimization of Boronic Acids as β-Lactamase Inhibitors

  摘要：

  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.

  DOI：

  10.1021/acs.jmedchem.5b00341
• 作为产物：
  描述：

  α-bromomethyl pinanediolboronate 在 sodium azide 、 四丁基溴化铵 、 zinc(II) chloride 作用下， 以 四氢呋喃 、 水 、 乙酸乙酯 为溶剂， 反应 18.0h， 生成 (+)-pinanediol (1R)-2-azido-1-[N,N-bis(trimethylsilyl)amino]ethaneboronate
  参考文献：
  名称：

  [EN] BORONIC ACID INHIBITORS OF BETA-LACTAMASES
  [FR] INHIBITEURS DE TYPE ACIDE BORONIQUE DE BÊTA-LACTAMASES

  摘要：

  这项发明涉及新型硼酸化合物，一种制备这种化合物的方法，用于制备这种化合物的中间化合物，用于制备这种化合物的方法中间化合物，一种药物组合物，上述一种或多种化合物或药物组合物在制造治疗细菌感染药物的药物制剂中的使用，以及一种筛选方法。

  公开号：

  WO2013053372A1

文献信息

• [EN] HETEROCYCLIC BORONIC ACID ESTER DERIVATIVES AND THERAPEUTIC USES THEREOF<br/>[FR] DÉRIVÉS D'ESTER D'ACIDE BORONIQUE HÉTÉROCYCLIQUE ET LEURS UTILISATIONS THÉRAPEUTIQUES
  申请人：REMPEX PHARMACEUTICALS INC

  公开号：WO2013033461A1

  公开（公告）日：2013-03-07

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

  本文揭示了抗微生物化合物组合物、药物组合物及其使用和制备。一些实施例涉及环硼酸酯化合物及其用作治疗剂的用途。
• Broad-spectrum cyclic boronate β-lactamase inhibitors featuring an intramolecular prodrug for oral bioavailability
  作者：K. Raja Reddy、Maxim Totrov、Olga Lomovskaya、David C. Griffith、Ziad Tarazi、Matthew C. Clifton、Scott J. Hecker

  DOI：10.1016/j.bmc.2022.116722

  日期：2022.5

  efforts to broaden the spectrum and potency of cyclic boronic acid β-lactamase inhibitor vaborbactam included a series of 7-membered ring boronates. Exploration of stereoisomers and incorporation of heteroatoms allowed identification of the all-carbon cyclic boronate with substituents trans as the preferred core structure, showing inhibition of Class A and C enzymes. Crystal structures of one analog

  早期扩大环状硼酸 β-内酰胺酶抑制剂 vaborbactam 的范围和效力的努力包括一系列 7 元环硼酸盐。对立体异构体的探索和杂原子的掺入允许鉴定具有取代基的全碳环状硼酸盐作为优选的核心结构，显示出对 A 类和 C 类酶的抑制作用。获得了与重要的β-内酰胺酶结合的一种类似物的晶体结构。当在酸性条件下分离时，这些化合物自发形成中性环状酸酐（分子内前药），与开环羧酸盐（9%）相比，其口服生物利用度（52-69%）显着提高。
• [EN] Β-LACTAMASE INHIBITORS AND USES THEREOF<br/>[FR] INHIBITEURS DE BÊTA-LACTAMASE ET LEURS UTILISATIONS
  申请人：UNIV CASE WESTERN RESERVE

  公开号：WO2022187362A1

  公开（公告）日：2022-09-09

  A pharmaceutical composition for use in treating a bacterial infection in a subject in need thereof includes a β-lactam antibiotic and boronic acid compound as described herein.

  一种用于治疗需要治疗细菌感染的患者的制药组合物，包括本文所述的β-内酰胺类抗生素和硼酸化合物。
• Synthesis of a Novel Boronic Acid Transition State Inhibitor, MB076: A Heterocyclic Triazole Effectively Inhibits <i>Acinetobacter</i>-Derived Cephalosporinase Variants with an Expanded-Substrate Spectrum
  作者：Rachel A. Powers、Cynthia M. June、Micah C. Fernando、Erin R. Fish、Olivia L. Maurer、Rachelle M. Baumann、Trevor J. Beardsley、Magdalena A. Taracila、Susan D. Rudin、Kristine M. Hujer、Andrea M. Hujer、Nicolò Santi、Valentina Villamil、Maria Luisa Introvigne、Fabio Prati、Emilia Caselli、Robert A. Bonomo、Bradley J. Wallar

  DOI：10.1021/acs.jmedchem.3c00144

  日期：2023.7.13

  structural and functional differences is essential. Equally as important is the development of compounds that inhibit all prevalent ADCs despite these differences. The boronic acid transition state inhibitor, MB076, a novel heterocyclic triazole with improved plasma stability, was synthesized and inhibits seven different ADC β-lactamase variants with Ki values <1 μM. MB076 acted synergistically in combination

  C 类不动杆菌衍生的头孢菌素酶 (ADC) 是抑制多重耐药病原体鲍曼不动杆菌的重要靶点。许多 ADC 变体已经出现，表征它们的结构和功能差异至关重要。同样重要的是开发能够抑制所有流行 ADC 的化合物，尽管存在这些差异。硼酸过渡态抑制剂MB076是一种新型杂环三唑，具有改善的血浆稳定性，可抑制七种不同的 ADC β-内酰胺酶变体，K i值 <1 μM。MB076与多种头孢菌素联合发挥协同作用以恢复敏感性。Ω 环中含有丙氨酸重复的 ADC 变体（特别是 ADC-33）对较大的头孢菌素（例如头孢他啶、头孢地洛考和头孢洛嗪）表现出增强的活性。本研究中 ADC 变体的 X 射线晶体结构为底物轮廓差异提供了结构背景，并表明抑制剂在所有 ADC 变体中采用相似的构象，尽管其活性位点附近的变化很小。
• Biochemical and Structural Analysis of Inhibitors Targeting the ADC-7 Cephalosporinase of <i>Acinetobacter baumannii</i>
  作者：Rachel A. Powers、Hollister C. Swanson、Magdalena A. Taracila、Nicholas W. Florek、Chiara Romagnoli、Emilia Caselli、Fabio Prati、Robert A. Bonomo、Bradley J. Wallar

  DOI：10.1021/bi500887n

  日期：2014.12.9

  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.