4-nitrobenzyl 3,5-dihydroxy-2-methylbenzoate | 147215-24-5

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 4-nitrobenzyl 3,5-dihydroxy-2-methylbenzoate
• 英文别名: p-nitrobenzyl 3,5-dihydroxy-2-methylbenzoate；(4-Nitrophenyl)methyl 3,5-dihydroxy-2-methylbenzoate
• CAS: 147215-24-5
• 化学式: C₁₅H₁₃NO₆
• 分子量: 303.271
• InChiKey: SQNVILOXTUFUDF-UHFFFAOYSA-N

物化性质

• 熔点：
  156-158 °C(Solv: ethyl acetate (141-78-6); hexane (110-54-3))
• 沸点：
  537.3±19.0 °C(Predicted)
• 密度：
  1.423±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  22
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.13
• 拓扑面积：
  113
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  4-nitrobenzyl 3,5-dihydroxy-2-methylbenzoate 在 N-溴代丁二酰亚胺(NBS) 、 三乙胺 作用下， 以 四氯化碳 、 N,N-二甲基甲酰胺 为溶剂， 反应 6.67h， 生成 4-nitrobenzyl 2-(bromomethyl)-3,5-bis[(tert-butyl)dimethylsilyloxy]benzoate
  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：

  3,5-dihydroxy-2-methylbenzoic acid 、 对硝基溴化苄 在 四甲基胍 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 72.5h， 以78%的产率得到4-nitrobenzyl 3,5-dihydroxy-2-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

• NOVEL DNA GYRASE INHIBITORS, PROCESS FOR THEIR MANUFACTURE AND PHARMACEUTICAL PREPARATIONS CONTAINING SAME
  申请人：F. HOFFMANN-LA ROCHE AG

  公开号：EP0535192A1

  公开（公告）日：1993-04-07
• US5294609A
  申请人：——

  公开号：US5294609A

  公开（公告）日：1994-03-15
• US5399741A
  申请人：——

  公开号：US5399741A

  公开（公告）日：1995-03-21
• US5486466A
  申请人：——

  公开号：US5486466A

  公开（公告）日：1996-01-23
• [EN] NOVEL DNA GYRASE INHIBITORS, PROCESS FOR THEIR MANUFACTURE AND PHARMACEUTICAL PREPARATIONS CONTAINING SAME
  申请人：F. HOFFMANN-LA ROCHE AG

  公开号：WO1992018490A1

  公开（公告）日：1992-10-29

  (EN) Bicyclic derivatives of general formula (I), wherein X1 is -S- or -SO-; X2 is -CO- or -CS-; R1 is hydrogen, halogen or lower alkyl optionally substituted by halogen or lower alkoxy; R2 and R3 are each independently hydrogen, lower alkyl, halogen, amino, lower alkylamino, di-lower alkylamino, acylamino, lower alkoxy, lower alkoxymethoxy or a group OR4; R4 is hydrogen or an easily hydrolyzable group; R5 is hydrogen, optionally esterified carboxy or amidated (thio)carboxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted acyl or heterocyclyl; R6 and R7a are each independently hydrogen or lowe alkyl; R7b is hydrogen, optionally substituted hydroxy, -NR-A or -N=B, in which R is hydrogen or lower alkyl, A is hydrogen, optionally substituted alkyl, lower cycloalkyl, iminoyl, (thio)acyl, esterified carboxy or amidated (thio)carboxy and B is lower alkylidene; R7a and R7b together represent oxo, lower alkoxycarbonylmethylidene or optionally substituted hydroxyimino; and R8 is hydrogen, optionally substituted alkyl, optionally esterified carboxy or amidated(thio)carboxy; provided that no more than two of R1-R3 are nitrogen-containing groups; no more than two of R1-R3 are oxygen containing groups and no more than two of R1-R3 are either nitrogen containing or oxygen containing groups; and pharmaceutically acceptable salts of the compounds of formula (I) carrying an acidic and/or basic substituent. The products are antimicrobially active.(FR) Dérivés bicycliques répondant à la formule générale (I), dans laquelle X1 représente -S- ou -SO-; X2 représente -CO- ou -CS-; R1 représente hydrogène, halogène ou alkyle inférieur éventuellement substitué par halogène ou alcoxy inférieur; R2 et R3 représentent, indépendamment l'un de l'autre, hydrogène, alkyle inférieur, halogène, amino, alkylamino inférieur, alkylamino di-inférieur, acylamino, alcoxy inférieur, alcoxyméthoxy inférieur ou un groupe OR4; R4 représente hydrogène ou un groupe facilement hydrolysable; R5 représente hydrogène, carboxy éventuellement estérifié ou (thio)carboxy amidé, alkyle éventuellement substitué, alcényle éventuellement substitué, acyle éventuellement substitué, ou hétérocyclyle; R6 et R7a représentent, indépendamment l'un de l'autre, hydrogène ou alkyle inférieur; R7b représente hydrogène, hydroxy éventuellement substitué, -NR-A ou-N=B, où R représente hydrogène ou alkyle inféireur, A représente hydrogène, alkyle éventuellement substitué, cycloalkyle inférieur, iminoyle, (thio)acyle, carboxy estérifié ou (thio)carboxy amidé, et B représente alkylidène inférieur; R7a et R7b ensemble représentent oxo, alcoxycarbonylméthylidène inférieur ou hydroxyimino éventuellement substitué; et R8 représente hydrogène, alkyle éventuellement substitué, carboxy éventuellement estérifié ou (thio)carboxy amidé; à condition que deux au maximum des éléments R1 à R3 soient des groupes contenant de l'azote; que deux au maximum des éléments R1 à R3 soient des groupes contenant de l'oxygène, et que deux au maximum des éléments R1 à R3 soient des groupes contenant soit de l'azote soit de l'oxygène; et les sels pharmaceutiquement acceptables des composés de la formule (I) portant un substituant acidifère et/ou basique. Ces produits présentent une activité antimicrobienne.