(2S,3R,4S,6R)-2-(((3R,4S,5S,6R,7R,9R,11S,12R,13S,14R)-10-(acetoxyimino)-14-ethyl-4,12,13-trihydroxy-7-methoxy-3,5,7,9,11,13-hexamethyl-2-oxooxacyclotetradecan-6-yl)oxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-yl acetate | 152235-06-8

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: (2S,3R,4S,6R)-2-(((3R,4S,5S,6R,7R,9R,11S,12R,13S,14R)-10-(acetoxyimino)-14-ethyl-4,12,13-trihydroxy-7-methoxy-3,5,7,9,11,13-hexamethyl-2-oxooxacyclotetradecan-6-yl)oxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-yl acetate
• CAS: 152235-06-8
• 化学式: C₃₄H₆₀N₂O₁₂
• 分子量: 688.857
• InChiKey: WYSBTCUCJLONIG-CFCNEJBASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.44
• 重原子数：
  48.0
• 可旋转键数：
  7.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.88
• 拓扑面积：
  182.88
• 氢给体数：
  3.0
• 氢受体数：
  14.0

反应信息

• 作为反应物：
  描述：

  (2S,3R,4S,6R)-2-(((3R,4S,5S,6R,7R,9R,11S,12R,13S,14R)-10-(acetoxyimino)-14-ethyl-4,12,13-trihydroxy-7-methoxy-3,5,7,9,11,13-hexamethyl-2-oxooxacyclotetradecan-6-yl)oxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-yl acetate 在 吡啶 、 N-氯代丁二酰亚胺 、 copper(l) iodide 、 二甲基硫 、 potassium tert-butylate 、 sodium hydride 、 三乙胺 作用下， 以 四氢呋喃 、 二氯甲烷 、 二甲基亚砜 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 54.66h， 生成 2-fluoro-3-O-descladinosyl-3-oxo-6-O-methylerythromycin A-9-O-[3-(1',4'-dihydro-4'-oxo-quinol-6'-yl)-2-propargyl]oxime-11,12-cyclic carbonate
  参考文献：
  名称：

  一种大环内酯和喹诺酮杂合物及其制备方法

  摘要：

  本发明提供一种大环内酯和喹诺酮杂合物，其特征在于，所述大环内酯和喹诺酮杂合物包括具有通式I和通式Ⅱ的化合物，或者，所述大环内酯和喹诺酮杂合物包括所述通式I和通式Ⅱ的化合物与无机酸或有机酸形成的药学可接受的盐，所述大环内酯和喹诺酮杂合物既能够较好的适应工业化生产，并且针对临床上常见的红霉素耐药的肺炎链球菌、金黄色葡萄球菌、化脓链球菌、卡他莫拉和嗜血流感菌等致病菌具有良好的抗敏感菌和抗耐药菌活性，能有效治疗临床细菌性肺炎或者其他微生物(如支原体、军团菌属等)引起的肺炎、以及其他组织感染；

  公开号：

  CN109942654B
• 作为产物：
  描述：

  、 乙酸酐 以 二氯甲烷 为溶剂， 以73.13%的产率得到(2S,3R,4S,6R)-2-(((3R,4S,5S,6R,7R,9R,11S,12R,13S,14R)-10-(acetoxyimino)-14-ethyl-4,12,13-trihydroxy-7-methoxy-3,5,7,9,11,13-hexamethyl-2-oxooxacyclotetradecan-6-yl)oxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-yl acetate
  参考文献：
  名称：

  Design, synthesis and structure-activity relationships of novel macrolones: Hybrids of 2-fluoro 9-oxime ketolides and carbamoyl quinolones with highly improved activity against resistant pathogens

  摘要：

  Constitutively erythromycin-resistant apathogens are more difficult to address than inducibly resistant and efflux-resistant strains. Three series of the 4th generation 2-fluoro 9-oxime erythromycin ketolides were synthesized and evaluated. Incorporation of substituted heteroaryl groups (a - m), in contrast to previously reported the unsubstituted heteroaryl groups, proved to the beneficial for enhancement of the activities of the 9-propgargyl ketolide 8 series and the 9-allyl ketolide 14 series. But these aryl groups (a - m) cannot supply the resulting compounds 8 and 14, unlike corresponding the 6-allyl ketolide 20 series, with activity against constitutively resistant Streptococcus pneumoniae. However, hybrids of macrolides and quinolones (8, 14 and 20, Ar = n - t) exhibited not only high activities against susceptible, inducibly erm-mediated resistant, and efflux-mediated resistant strains, but also significantly improved potencies against constitutively resistant Streptococcus pneumoniae and Streptococcus pyogenes. The capacity was highlighted by introduction of newly designed carbamoyl quinolones (q, r, s and t) rather than commonly seen carboxy quinolones (o and p) as the pharmacophores. Structure-activity relationships and molecular modelling indicated that 8r, 14r and 20q may have different binding sites compared to current erythromycins. Moreover, 8r, 14r and 20q have 2.5-3.6 times prolonged half-life and 2.3- to 2.6-fold longer mean residence time in vivo over telithromycin. These findings pave the way for rational design of novel non-telithromycin macrolides that target new binding sites within bacterial ribosomes. (C) 2019 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2019.02.073

文献信息

• Synthesis and structure-bactericidal activity relationships of non-ketolides: 9-Oxime clarithromycin 11,12-cyclic carbonate featured with three-to eight-atom-length spacers at 3-OH
  作者：Xue-Meng Li、Wei Lv、Si-Yang Guo、Ya-Xin Li、Bing-Zhi Fan、Mark Cushman、Fan-Sheng Kong、Jun Zhang、Jian-Hua Liang

  DOI：10.1016/j.ejmech.2019.03.037

  日期：2019.6

  general, potent non-ketolide versions of erythromycin possessed conformationally constricted two- or three-atom-length sidechains at 3-OH. Novel 14-membered non-ketolides possessing long spacers beyond three-atom length were evaluated for antibacterial activity. The most potent one is 34a, featuring a five-atom-length flexible linker from of a pyridine ring to the aglycone. Conversion of the pyridine

  通常，有效的非酮类版本的红霉素在3-OH处具有构象收缩的两个或三个原子长的侧链。评估了具有超过三个原子长度的长间隔基的新型14元非酮类化合物的抗菌活性。最有效的一个是34a，它具有一个从吡啶环到糖苷配基的五原子长的柔性接头。34a的吡啶转化为其他芳基，将34a的连接长度更改为更长或更短的连接，以及连接物对刚性烯烃或炔烃的柔性变化，导致抗菌活性降低。大环内酯与喹诺酮类化合物28b，31和34b的杂种与34a相比，拥有15条成员的不同侧链的人效率低下。与市售的酮内酯泰利霉素相似，非酮内酯34a被证明是一种时间依赖性杀菌剂，但它具有优异的体内药代动力学特性，例如更长的半衰期，更高的血浆浓度，更低的清除率和更短的时间以达到最高相对于泰利霉素的药物浓度。分子对接提示34a可能π-π与细菌核糖体RNA碱基G2505Ec相互作用。这项研究表明，可以对抑菌剂红霉素进行结构修饰，以提供针对核糖体的新型杀菌化
• 一种含有大环内酯基的喹喏酮衍生物、制备方法及应用
  申请人：北京理工大学

  公开号：CN111574575B

  公开（公告）日：2022-05-17

  本发明提供了一种含有大环内酯基的喹喏酮衍生物、制备方法及应用。其中，所述含有大环内酯基的喹喏酮衍生物为具有下述通式Ⅰ的化合物，或所述含有大环内酯基的喹喏酮衍生物为可接受的盐，所述可接受的盐由具有所述通式Ⅰ的化合物与无机酸或有机酸形成；其中，R包括1‑6元烷基、1‑6元杂烷基、3‑6元环烷基、3‑6元杂环烷基、3元烯烃基、3元炔基、末端连接杂芳基的1‑6元烷基、3元烯烃基、3元炔基、末端连接取代杂芳基的1‑6元烷基、3元烯烃基、3元炔基中的一种。本发明提供的喹喏酮衍生物，不但保留了对敏感菌的抗菌活性，恢复了对诱导耐药菌的活性，同时还提高了对高耐药水平的组成型耐药菌的抗菌活性。
• Design, synthesis and structure-bactericidal activity relationships of novel 9-oxime ketolides and reductive epimers of acylides
  作者：Jing-Chao Tian、Xu Han、Wei Lv、Ya-Xin Li、Hui Wang、Bing-Zhi Fan、Mark Cushman、Jian-Hua Liang

  DOI：10.1016/j.bmcl.2017.02.041

  日期：2017.4

  Erythromycin was long viewed as a bacteriostatic agent. The erythromycin derivatives, 9-oxime ketolides have a species-specific bactericidal profile. Among them, the 3'-allyl version of the 9-oxime ketolide 1 (Ar = 3-quinolyl; 17a) is bactericidal against Streptococcus pneumoniae and Streptococcus pyogenes. In contrast, the 2-fluoro analogs of 1, 13a (Ar = 6-quinolyl), 13b (Ar = 3-quinolyl) and 24a (Ar = 4-isoquinolyl), show bactericidal activities against S. pneumoniae, Staphylococcus aureus and Moraxella catarrhalis, while the 2-fluoro analogs 13c (Ar = 3-aminopyridyl) and 24b (Ar = 3-carbamoylpyridyl) are only bactericidal against S. pneumoniae and Haemophilus influenzae. Reduction of the ketolides led to novel epiacylides, the 3-O-epimers of the acylides. Alteration of linker length (30b vs. 30a), 2-fluorination (33 vs. 30a) and incorporation of additional spacers at the 9-oxime or 6-OH (35, 40 vs. 30a) did not restore the epiacylides back to be as active as the acylide 31. Molecular docking suggested that epimerization at the 3 position reshapes the orientation of the 3-v-sidechain and leads to considerably weaker binding with bacterial ribosomes. (C) 2017 Elsevier Ltd. All rights reserved.
• Synthesis and antibacterial activities of 6-O-methylerythromycin A 9-O-(3-aryl-2-propenyl) oxime ketolide, 2,3-enol ether, and alkylide analogues
  作者：Jian-Hua Liang、Li-Jing Dong、He Wang、Kun An、Xiao-Li Li、Li Yang、Guo-Wei Yao、Ying-Chun Xu

  DOI：10.1016/j.ejmech.2010.05.008

  日期：2010.9

  A facile and efficient route was presented to achieve 3-keto-clarithromycin 9-O-(3-aryl-E-2-propenyl) oxime derivatives 8, 2,3-dehydro-3-O-allyl-clarithromycin 9-O-(3-aryl-E-2-propenyl) oxime derivatives 11, and 3-O-allyl-clarithromycin 9-O-(3-aryl-E-2-propenyl) oxime derivatives 12. Among them, compound 8, particularly 8d (Ar = 6-quinolyl), exhibited improved antibacterial activities against erythromycin-susceptible Staphylococcus aureus and Streptococcus pneumoniae, and greatly enhanced activities against the resistant strains encoded by erm and mef genes, as compared to clarithromycin and azithromycin. (C) 2010 Elsevier Masson SAS. All rights reserved.