(+)-pinanediol (1R)-2-azido-1-[(2-thienylacetyl)amino]ethaneboronate | 1425968-44-0

• 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-[(2-thienylacetyl)amino]ethaneboronate
• 英文别名: N-[(1R)-2-azido-1-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]decan-4-yl]ethyl]-2-(2-thienyl)acetamide；N-[(1R)-2-azido-1-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]decan-4-yl]ethyl]-2-thiophen-2-ylacetamide
• CAS: 1425968-44-0
• 化学式: C₁₈H₂₅BN₄O₃S
• 分子量: 388.298
• InChiKey: WMCRMAWGJFNVMY-HMZURLEKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.35
• 重原子数：
  27
• 可旋转键数：
  6
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.72
• 拓扑面积：
  90.2
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (+)-pinanediol (1R)-2-azido-1-[(2-thienylacetyl)amino]ethaneboronate 在 盐酸 、 platinum(IV) oxide 、 氢气 、 三乙酰氧基硼氢化钠 作用下， 以 1,4-二氧六环 、 1,2-二氯乙烷 为溶剂， 反应 0.17h， 生成 tert-butyl 3-[tert-butyl(dimethyl)silyl]oxy-4-[[(2R)-2-[[2-(2-thienyl)acetyl]amino]-2-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]decan-4-yl]ethyl]amino]butanoate
  参考文献：
  名称：

  广谱环状硼酸盐β-内酰胺酶抑制剂，具有用于口服生物利用度的分子内前药

  摘要：

  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。

  DOI：

  10.1016/j.bmc.2022.116722
• 作为产物：
  描述：

  (S)-pinanediol (2-azido-1-chloroethyl)boronate 在 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 四氢呋喃 、 正己烷 、 二氯甲烷 为溶剂， 反应 0.5h， 生成 (+)-pinanediol (1R)-2-azido-1-[(2-thienylacetyl)amino]ethaneboronate
  参考文献：
  名称：

  广谱环状硼酸盐β-内酰胺酶抑制剂，具有用于口服生物利用度的分子内前药

  摘要：

  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。

  DOI：

  10.1016/j.bmc.2022.116722

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。
• [EN] BORONIC ACID INHIBITORS OF BETA-LACTAMASES<br/>[FR] INHIBITEURS DE TYPE ACIDE BORONIQUE DE BÊTA-LACTAMASES
  申请人：THERABOR PHARMACEUTICALS

  公开号：WO2013053372A1

  公开（公告）日：2013-04-18

  The invention relates to novel boronic acid compounds, a method for the preparation of such compounds, intermediate compounds for the preparation of such compounds, intermediate compounds for the use in a method for preparation of such compounds, a pharmaceutical composition, the use of one or more compounds discussed above or of a pharmaceutical composition in the manufacture of a medicament for the treatment of a bacterial infection, and a screening method.

  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。
• 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.
• 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.
• 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。