allyl 2-{(R)-2-[3-(allyloxycarbonylaminomethyl)-1,2,4-oxadiazol-5-yl]-2-amino-ethylsulfanylmethyl}-3-[dimethyl(thexyl)silyloxy]-5-methoxy-6-methylbenzoate | 173153-52-1

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 英文名称: allyl 2-{(R)-2-[3-(allyloxycarbonylaminomethyl)-1,2,4-oxadiazol-5-yl]-2-amino-ethylsulfanylmethyl}-3-[dimethyl(thexyl)silyloxy]-5-methoxy-6-methylbenzoate
• 英文别名: allyl (R)-2-[2-amino-2-(3-allyloxycarbonylaminomethyl-1,2,4-oxadiazol-5-yl)ethylsulfanylmethyl]-3-[dimethyl(thexyl)silyloxy]-5-methoxy-6-methylbenzoate；prop-2-enyl 2-[[(2R)-2-amino-2-[3-[(prop-2-enoxycarbonylamino)methyl]-1,2,4-oxadiazol-5-yl]ethyl]sulfanylmethyl]-3-[2,3-dimethylbutan-2-yl(dimethyl)silyl]oxy-5-methoxy-6-methylbenzoate
• CAS: 173153-52-1
• 化学式: C₃₀H₄₆N₄O₇SSi
• 分子量: 634.869
• InChiKey: KBTVHHOPAXQVDL-QFIPXVFZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.09
• 重原子数：
  43
• 可旋转键数：
  19
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  173
• 氢给体数：
  2
• 氢受体数：
  11

反应信息

• 作为反应物：
  描述：

  allyl 2-{(R)-2-[3-(allyloxycarbonylaminomethyl)-1,2,4-oxadiazol-5-yl]-2-amino-ethylsulfanylmethyl}-3-[dimethyl(thexyl)silyloxy]-5-methoxy-6-methylbenzoate 在 劳森试剂 、 N-甲基吗啉 、 N-(三甲基硅基)吗啉 、 甲醇 、 氟化铵 、 四(三苯基膦)钯 、 N,N-二甲基三甲基硅胺 、 三甲基硅乙酸酯 、 三氟乙酸三甲基硅酯 、 对甲苯磺酸 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 、 三苯基膦 、 偶氮二甲酸二乙酯 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 甲苯 、 乙腈 为溶剂， 反应 26.5h， 生成 (R)-4-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-1,3,4,5,6,7,8,9,10,12-decahydro-16-hydroxy-14-methoxy-13-methyl-6-thioxo-11,2,5-benzoxathiaazacyclotetradecin-12-one
  参考文献：
  名称：

  New Antibacterial Agents Derived from the DNA Gyrase Inhibitor Cyclothialidine

  摘要：

  Cyclothialidine (1, Ro 09-1437) is a potent DNA gyrase inhibitor that was isolated from Streptomyces filipinensis NR0484 and is a member of a new family of natural products. It acts by competitively inhibiting the ATPase activity exerted by the B subunit of DNA gyrase but barely exhibits any growth inhibitory activity against intact bacterial cells, presumably due to insufficient permeation of the cytoplasmic membrane. To explore the antibacterial potential of 1, we developed a flexible synthetic route allowing for the systematic modification of its structure. From a first set of analogues, structure-activity relationships (SAR) were established for different substitution patterns, and the 14-hydroxylated, bicyclic core (X) of 1 seemed to be the structural prerequisite for DNA gyrase inhibitory activity. The variation of the lactone ring size, however, revealed that activity can be found among 11- to 16-membered lactones, and even seco-analogues were shown to maintain some enzyme inhibitory properties, thereby reducing the minimal structural requirements to a rather simple, hydroxylated benzyl sulfide (XI). On the basis of these "minimal structures" a modification program afforded a number of inhibitors that showed in vitro activity against Gram-positive bacteria. The best activities were displayed by 14-membered lactones, and representatives of this subclass exhibit excellent and broad in vitro antibacterial activity against Gram-positive pathogens, including Staphylococcus aureus, Streptococcus pyogenes, and Enterococcus faecalis, and overcome resistance against clinically used drugs. By improving the pharmacokinetic properties of the most active compounds (94, 97), in particular by lowering their lipophilic properties, we were able to identify congeners of cyclothialidine (1) that showed efficacy in vivo.

  DOI：

  10.1021/jm0310232
• 作为产物：
  描述：

  bis-[(R)-2-tert-butoxycarbonylamino-2-(3-allyloxycarbonylaminomethyl-1,2,4-oxadiazol-5-yl)ethyl] disulfide 在 三乙基硅烷 、 三丁基膦 、 三氟乙酸 作用下， 以 二氯甲烷 、 2,2,2-三氟乙醇 、 水 为溶剂， 反应 20.0h， 生成 allyl 2-{(R)-2-[3-(allyloxycarbonylaminomethyl)-1,2,4-oxadiazol-5-yl]-2-amino-ethylsulfanylmethyl}-3-[dimethyl(thexyl)silyloxy]-5-methoxy-6-methylbenzoate
  参考文献：
  名称：

  New Antibacterial Agents Derived from the DNA Gyrase Inhibitor Cyclothialidine

  摘要：

  Cyclothialidine (1, Ro 09-1437) is a potent DNA gyrase inhibitor that was isolated from Streptomyces filipinensis NR0484 and is a member of a new family of natural products. It acts by competitively inhibiting the ATPase activity exerted by the B subunit of DNA gyrase but barely exhibits any growth inhibitory activity against intact bacterial cells, presumably due to insufficient permeation of the cytoplasmic membrane. To explore the antibacterial potential of 1, we developed a flexible synthetic route allowing for the systematic modification of its structure. From a first set of analogues, structure-activity relationships (SAR) were established for different substitution patterns, and the 14-hydroxylated, bicyclic core (X) of 1 seemed to be the structural prerequisite for DNA gyrase inhibitory activity. The variation of the lactone ring size, however, revealed that activity can be found among 11- to 16-membered lactones, and even seco-analogues were shown to maintain some enzyme inhibitory properties, thereby reducing the minimal structural requirements to a rather simple, hydroxylated benzyl sulfide (XI). On the basis of these "minimal structures" a modification program afforded a number of inhibitors that showed in vitro activity against Gram-positive bacteria. The best activities were displayed by 14-membered lactones, and representatives of this subclass exhibit excellent and broad in vitro antibacterial activity against Gram-positive pathogens, including Staphylococcus aureus, Streptococcus pyogenes, and Enterococcus faecalis, and overcome resistance against clinically used drugs. By improving the pharmacokinetic properties of the most active compounds (94, 97), in particular by lowering their lipophilic properties, we were able to identify congeners of cyclothialidine (1) that showed efficacy in vivo.

  DOI：

  10.1021/jm0310232

文献信息

• A New DNA Gyrase Inhibitor Subclass of the Cyclothialidine Family Based on a Bicyclic Dilactam−Lactone Scaffold. Synthesis and Antibacterial Properties
  作者：Peter Angehrn、Erwin Goetschi、Hans Gmuender、Paul Hebeisen、Michael Hennig、Bernd Kuhn、Thomas Luebbers、Peter Reindl、Fabienne Ricklin、Anne Schmitt-Hoffmann

  DOI：10.1021/jm1014023

  日期：2011.4.14

  The DNA gyrase inhibitor cyclothialidine had been shown to be a valuable lead structure for the discovery of new antibacterial classes able to overcome bacterial resistance to clinically used drugs. Bicyclic lactone derivatives containing in their 12−14-membered ring a thioamide functionality were reported previously to exhibit potent antibacterial activity against Gram-positive bacteria. Moderate

  对于发现能够克服细菌对临床使用药物的耐药性的新型抗菌剂而言，DNA回旋酶抑制剂环噻啶已被证明是有价值的先导结构。先前已报道在其12-14元环中含有硫酰胺官能团的双环内酯衍生物对革兰氏阳性细菌表现出有效的抗菌活性。然而，仅对于带有亲水性取代基的衍生物证明了中等的体内功效，发现该衍生物对药物动力学具有有利的影响，并减少了代谢降解，特别是葡萄糖醛酸化。将一个额外的酰胺单元掺入环噻啶类似物的14元单内酰胺-内酯支架中，提供了一种新的固有的极性更高的DNA促旋酶抑制剂“双内酰胺”亚类。