- New Structure-Activity Relationships of the Quinolone Antibacterials Using the Target Enzyme. The Development and Application of a DNA Gyrase Assay
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A series of 60 newly synthesized and known quinolone antibacterials, including quinoline- and 1,8-naphthyridine-3-carboxylic acids, pyridopyrimidine-6-carboxylic acids, and some monocyclic 4-pyridone-3-carboxylic acids, were tested and compared in a newly established, easy to perform, DNA gyrase assay.The results were correlated with minimum inhibitory concentracions (MICs) against a variety of organisms.Among the known quinolones were 14 clinically significant drugs (oxolinic acid, norfloxacin, ciprofloxacin, enoxacin, etc.) which were used as standards and compared side- by-side.The study focused on the changes in DNA gyrase inhibition brought about by certain features of the molecules, namely, the C6-fluorine or the nature of the C7 substituent.The intrinsic gyrase inhibition of the fused parent rings, quinoline vs. naphthyridine vs. pyridopyrimidine, was also explored.In all cases, loss of enzyme inhibition produced poor MICs, but some compounds with good DNA gyrase inhibition did not correspondingly inhibit bacterial growth.Possible explanations for this phenomena and the benefits of a DNA gyrase-MIC strategy for developing future structure-activity relationships are discussed.
- Domagala, John M.,Hanna, Lori Doyle,Heifetz, Carl L.,Hutt, Marland P.,Mich, Thomas F.,et al.
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- Synthesis of Antimicrobial Agents. 1. Syntheses and Antibacterial Activities of 7-(Azole substituted)quinolones
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A series of 6-fluoro- and 6,8-difluoro-7-(azole substituted)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acids were prepared.Structure-activity relationship studies indicated that the antibacterial potency was better when the 6,8-substituents were fluorine atoms and the 7-substituent was either 1-imidazolyl, 20, or 4-methyl-1-imidazolyl, 25.From the results of studies on pharmacokinetic profile and toxicity, 20 and 25 were found to possess excellent antibacterial activities and to show high blood levels after oral administration to mice with low toxicity.
- Uno, Toshio,Takamatsu, Masanori,Inoue, Yoshimasa,Kawahata, Yoshihiro,Iuchi, Koji,Tsukamoto, Goro
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p. 2163 - 2169
(2007/10/02)
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- 7-(1-Pyrrolyl) derivatives of 1-ethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acids and 1-ethyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acids and their use as antimicrobial agents
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The present invention relates to new derivatives of 7-(1-pyrrolyl)-1-ethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 7-(1-pyrrolyl)-1-ethyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid of general formula I: STR1 in which: X represents a carbon atom or a nitrogen atom, and R represents a hydrogen atom or a fluorine atom, as well as their physiologicaly acceptable alkali metal salts or alkaline earth metal salts. The derivatives of the present invention are advantageously used as antimicrobial agents, espcially as anti-bacterial and anti-fungal agents.
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