1-methyl-7-fluoro-1,4-dihydro-4-oxo-8-[1'-(4'-N-(succinyloxymethyleneoxycarbonyl)piperazinyl)]-3-benzo[b][1,8]naphthyridinecarboxylic acid | 353289-30-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: 1-methyl-7-fluoro-1,4-dihydro-4-oxo-8-[1'-(4'-N-(succinyloxymethyleneoxycarbonyl)piperazinyl)]-3-benzo[b][1,8]naphthyridinecarboxylic acid
• 英文别名: 8-[4-(3-Carboxypropanoyloxymethoxycarbonyl)piperazin-1-yl]-7-fluoro-1-methyl-4-oxobenzo[b][1,8]naphthyridine-3-carboxylic acid
• CAS: 353289-30-2
• 化学式: C₂₄H₂₃FN₄O₉
• 分子量: 530.466
• InChiKey: ODIWVEGAMHIWCV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  38
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  167
• 氢给体数：
  2
• 氢受体数：
  13

反应信息

• 作为反应物：
  描述：

  1-methyl-7-fluoro-1,4-dihydro-4-oxo-8-[1'-(4'-N-(succinyloxymethyleneoxycarbonyl)piperazinyl)]-3-benzo[b][1,8]naphthyridinecarboxylic acid 、 aminopyoverdin 在 N-甲基哌啶 、 氯甲酸异丁酯 、 乙二胺四乙酸 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 28.0h， 以40%的产率得到
  参考文献：
  名称：

  Synthesis and Activities of Pyoverdin−Quinolone Adducts: A Prospective Approach to a Specific Therapy Against Pseudomonas aeruginosa

  摘要：

  Pseudomonas aeruginosa is particularly resistant to most all the antibiotics presently available, essentially because of the very low permeability of its outer membrane. To overcome this, we synthesized four siderophore-based antibiotics formed by two quinolones - norfloxacin and benzonaphthyridone - bound to the pyoverdin of P. aeruginosa ATCC 15692 via two types of spacer arms: one stable and the other readily hydrolyzable. From the comparison of their antibacterial properties with those of the two unbound quinolones, we reached the following conclusions: (a) The adducts inhibit Escherichia: coli's gyrase showing that the dissociation of the compounds is not necessary for their activity. However, the presence of the pyoverdin moiety on the molecule decreases the inhibition activity compared to the antibiotic alone. (b) They facilitate the uptake of Fe-55 using the specific pyoverdin-mediated iron-transport system of the bacterium. No uptake was observed either with II? aeruginosa ATCC 27853, which produces a structurally different pyoverdin, or with P. aeruginosa K690, which is a mutant of P. aeruginosa ATCC 15692 lacking FpvA, the outer-membrane pyoverdin receptor. (c) MIC determinations have shown that only strains P. aeruginosa ATCC 15692 and the derived outer-membrane receptor-producing but pyoverdin-deficient P. aeruginosa IA1 mutant present higher susceptibility to the pyoverdin-quinolone adducts, whereas P. aeruginosa ATCC 27853 and K690 are much more resistant. (d) Growth inhibition by these adducts confirmed these results and showed that the adducts with the hydrolyzable spacer arm have better activity than those with the stable one and that the labile spacer arm adducts present much higher activity than the quinolones alone. These results show clearly that the penetration of the antibiotic into the cells is favored when this latter is coupled with pyoverdin: Only the strains possessing the appropriate outer-membrane receptor present higher susceptibility to the adduct. In this case the antibiotic uses the pyoverdin-mediated iron-transport system. Furthermore, better efficiency is obtained when the spacer arm is liabile and favors the antibiotic release inside the cell, allowing better inhibition of gyrase.

  DOI：

  10.1021/jm990508g
• 作为产物：
  描述：

  1-methyl-7-fluoro-1,4-dihydro-4-oxo-8-[1'-(4'-N-(chloromethyloxycarbonyl)piperazinyl)]-3-benzo[b][1,8]naphthyridinecarboxylic acid 在 1,8-双二甲氨基萘 、 三氟乙酸 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 26.0h， 生成 1-methyl-7-fluoro-1,4-dihydro-4-oxo-8-[1'-(4'-N-(succinyloxymethyleneoxycarbonyl)piperazinyl)]-3-benzo[b][1,8]naphthyridinecarboxylic acid
  参考文献：
  名称：

  Synthesis and Activities of Pyoverdin−Quinolone Adducts: A Prospective Approach to a Specific Therapy Against Pseudomonas aeruginosa

  摘要：

  Pseudomonas aeruginosa is particularly resistant to most all the antibiotics presently available, essentially because of the very low permeability of its outer membrane. To overcome this, we synthesized four siderophore-based antibiotics formed by two quinolones - norfloxacin and benzonaphthyridone - bound to the pyoverdin of P. aeruginosa ATCC 15692 via two types of spacer arms: one stable and the other readily hydrolyzable. From the comparison of their antibacterial properties with those of the two unbound quinolones, we reached the following conclusions: (a) The adducts inhibit Escherichia: coli's gyrase showing that the dissociation of the compounds is not necessary for their activity. However, the presence of the pyoverdin moiety on the molecule decreases the inhibition activity compared to the antibiotic alone. (b) They facilitate the uptake of Fe-55 using the specific pyoverdin-mediated iron-transport system of the bacterium. No uptake was observed either with II? aeruginosa ATCC 27853, which produces a structurally different pyoverdin, or with P. aeruginosa K690, which is a mutant of P. aeruginosa ATCC 15692 lacking FpvA, the outer-membrane pyoverdin receptor. (c) MIC determinations have shown that only strains P. aeruginosa ATCC 15692 and the derived outer-membrane receptor-producing but pyoverdin-deficient P. aeruginosa IA1 mutant present higher susceptibility to the pyoverdin-quinolone adducts, whereas P. aeruginosa ATCC 27853 and K690 are much more resistant. (d) Growth inhibition by these adducts confirmed these results and showed that the adducts with the hydrolyzable spacer arm have better activity than those with the stable one and that the labile spacer arm adducts present much higher activity than the quinolones alone. These results show clearly that the penetration of the antibiotic into the cells is favored when this latter is coupled with pyoverdin: Only the strains possessing the appropriate outer-membrane receptor present higher susceptibility to the adduct. In this case the antibiotic uses the pyoverdin-mediated iron-transport system. Furthermore, better efficiency is obtained when the spacer arm is liabile and favors the antibiotic release inside the cell, allowing better inhibition of gyrase.

  DOI：

  10.1021/jm990508g

文献信息

• Synthesis and Activities of Pyoverdin−Quinolone Adducts: A Prospective Approach to a Specific Therapy Against <i>Pseudomonas a</i><i>eruginosa</i>
  作者：Christophe Hennard、Que Chi Truong、Jean-François Desnottes、Jean-Marc Paris、Nicole J. Moreau、Mohamed A. Abdallah

  DOI：10.1021/jm990508g

  日期：2001.6.1

  Pseudomonas aeruginosa is particularly resistant to most all the antibiotics presently available, essentially because of the very low permeability of its outer membrane. To overcome this, we synthesized four siderophore-based antibiotics formed by two quinolones - norfloxacin and benzonaphthyridone - bound to the pyoverdin of P. aeruginosa ATCC 15692 via two types of spacer arms: one stable and the other readily hydrolyzable. From the comparison of their antibacterial properties with those of the two unbound quinolones, we reached the following conclusions: (a) The adducts inhibit Escherichia: coli's gyrase showing that the dissociation of the compounds is not necessary for their activity. However, the presence of the pyoverdin moiety on the molecule decreases the inhibition activity compared to the antibiotic alone. (b) They facilitate the uptake of Fe-55 using the specific pyoverdin-mediated iron-transport system of the bacterium. No uptake was observed either with II? aeruginosa ATCC 27853, which produces a structurally different pyoverdin, or with P. aeruginosa K690, which is a mutant of P. aeruginosa ATCC 15692 lacking FpvA, the outer-membrane pyoverdin receptor. (c) MIC determinations have shown that only strains P. aeruginosa ATCC 15692 and the derived outer-membrane receptor-producing but pyoverdin-deficient P. aeruginosa IA1 mutant present higher susceptibility to the pyoverdin-quinolone adducts, whereas P. aeruginosa ATCC 27853 and K690 are much more resistant. (d) Growth inhibition by these adducts confirmed these results and showed that the adducts with the hydrolyzable spacer arm have better activity than those with the stable one and that the labile spacer arm adducts present much higher activity than the quinolones alone. These results show clearly that the penetration of the antibiotic into the cells is favored when this latter is coupled with pyoverdin: Only the strains possessing the appropriate outer-membrane receptor present higher susceptibility to the adduct. In this case the antibiotic uses the pyoverdin-mediated iron-transport system. Furthermore, better efficiency is obtained when the spacer arm is liabile and favors the antibiotic release inside the cell, allowing better inhibition of gyrase.