Quinolones

Quinolones are a group of structurally similar antimicrobial drugs that exhibit high activity against many microorganisms.

Formally, the first representative of the new class of antimicrobial drugs (called drugs of the quinolone series, which are derivatives of naphthiridine), was nalidixic acid (nevi-gramon), which was synthesized in 1962 and was suggested for treating urinary tract infections. The main spectrum of its use includes Gram-negative bacteria. It is also effective with respect to colon bacillus, proteus, klebisella, shigella, and salmonella. In recent years a number of chemically similar compounds have been synthesized, such as oxolinic acid (strictly speaking, a derivative of quinolone) and cinoxacin (a derivative of quinolone), although all of them had a relatively narrow antimicrobial spectrum.

Enormous progress was made in the 1980s due to the introduction of a fluorine atom to the C6 position of 4-quinolone and a piperazine fragment to the C7 position. Introducing a fluorine atom in the indicated position dramatically increased the activity of the drug with respect to Gram-positive microorganisms, which broadened its spectrum of action to include Gram-negative microorganisms. Introducing the piperazine fragment to C7 ensured activity of this group of drugs with respect to Pseudomonas aeruginosa. The sub-stituents at the nitrogen atom of the quinolone structure and in the piperazine ring may vary from drug to drug.

All fluoroquinolones are usable in medical practice: ciprofloxacin, enoxacin, norfloxacin, and ofloxacin have approximately the same antimicrobial spectrum, which includes most aerobic Gram-negative and a few Gram-positive bacteria. Fluoroquinolones are highly active against most enterobacteria, including E. coli, Enterobacter, Proteus mirabilis, Proteus vul-garis, Morganella morganii, Providencia, Citrobacter and Serratia. They are also active with respect to Pseudomonas aeruginosa, including strains resistant to other antibacterial drugs. Most strains of Acinetobacter, aerobic Gram-negative microorganisms are sensitive to fluo-roquinolones. Fluoroquinolones are highly active against most Gram-negative bacterial pathogens of the gastrointestinal tract, such as Shigella, Salmonella, Yersinia enterocolitica, Aeromonas species, and Vibrio species. Gram-negative coccobacteria Haemophilus influen-zae, Haemophilus ducreyi and Gram-negative cocci Neisseria meningitides, N. gonorrhoeae, and Moraxella are also very sensitive to fluoroquinolones. Fluoroquinolones are also active with respect to most Gram-positive bacteria, Staphylococcus aureus and S. epidermidis, although the concentrations used must be somewhat higher than for Gram-negative bacterial pathogens.

Fluoroquinolones are powerful bactericidal drugs that change the structure and function of bacterial DNA by affecting the enzyme DNA-gyrase (topoisomerase II). This enzyme is responsible for negative supercoiling twisting (negative supercoiling) to covalently closed, circular DNA as well as breaking up the repeating compounds (catenation, decatenation) of DNA coils linked to the chain. DNA-gyrase is capable of breaking down bacterial DNA that has an approximate length of 1300 |im, such as in E. coli, inside a cell whose size ranges from 2 to 3 |im. This enzyme is necessary for replication, restoration, and transcription of certain DNA operons. DNA-gyrase is made up of two A and two B subunits. Quinolones have a direct effect on the function of A subunits.

As was already mentioned, drugs of this series have a similar antimicrobial spectrum, which includes most aerobic Gram-negative and a few Gram-positive bacteria. The specific difference in activity of these drugs is observed with respect to a few specific microorganisms, their relative toxicity, pharmacokinetic features, and so on. For example, ciprofloxacin and norfloxacin have a similar antimicrobial spectrum; however, depending on the type of microorganisms, norfloxacin can turn out to be 2-8 times weaker.

Two mechanisms of resistance have been discovered with respect to fluoro-quinolones: a change in subunits A of DNA-gyrase, and reduced permeability of the outer membrane of the bacteria. Resistance is mediated by chromosomes, and not plas-mids in the bacteria. The development of resistance while using the drugs is very rarely observed.

Because of its pharmacokinetic features (pronounced bioaccessability upon oral use, diffusion to tissues and permeation into them, broad spectrum of antibacterial activity, and so on), fluoroquinolones have considerable potential for treating infections of practically any anatomic localization. Fluoroquinolones are very effective in treating infections of the respiratory tract, urinary tract, bones, skin, soft tissues, and so on.

Nalidixic acid: Nalidixic acid, 1-ethyl-1,4-dihydro-7-methyl-4-oxo-1,8-naphthiridin-3-carboxylic acid (33.2.4), is synthesized by the following scheme. In the first stage, the reaction of 2-amino-6-methylpyridine and diethyl ethoxymethylenemalonate forms the substituted product (33.2.1), which when heated cyclizes to ethyl ester of 4-hydroxy -7-methyl-1,8-napthiridin-3-carboxylic acid (33.2.2). Hydrolyzing the resulting product with a base gives the corresponding acid (33.2.3). Alkylating this with ethyl iodide in the presence of potassium hydroxide gives nalidixic acid [60-64].

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