Antibacterials quinolone

Over 10000 quinolone antibacterial agents have now been synthesized. Nalidixic acid is regarded as the progenitor of the new quinolones. It has been used for several years as a clinically important drug in the treatment of urinary tract infections. Since its clinical introduction, other 4-quinolone antibacterials have been synthesized, some of which show considerably greater antibacterial potency. Furthermore, this means that many types of bacteria not susceptible to nahdixic acid therapy m be sensihve to the newer derivahves. The most important development was the introduction of a fluorine substituent at C-6, which led to a considerable increase in potency and spectrum of activity compared with nalidixic add. These second-generation quinolones are known as fluoroquinolones, examples of which are ciprofloxacin and norfloxacin (Fig. 5.19). 

Antacids form insoluble metal ion chelates with tetracyclines, 4-quinolone antibacterials and penicillamine. 

Rizk M. Belal F. Ibrahim F. et al Derivative spectrophotometric analysis of 4-quinolone antibacterials in... 

Table 1. Commercially Significant Quinolone Antibacterial Agents...

Another important development in the stmcture—activity relationships of quinolone antibacterials came with the introduction of the 1,8-bridged quinolone ofloxacin (6a). In this quinolone, the movement of the ethyl group at the 1-position is restricted by "tying" it to the 8-position in the form of a 1,4-benzoxazine ring. In vitro activity improvements are found that are more or less comparable to the improvements noted with ciprofloxacin (35,41—43). 

When ofloxacin was first introduced it was made available as the racemate. Later the optical isomers were prepared and it was found that the (3)-enantiomer, DR 3355 (6b), was substantially more active (8—128-fold) than the (R)-isomer against a broad range of bacteria (47—50). This chiral preference is not unique to ofloxacin and has been demonstrated in other quinolones as well (51,52). This significant finding has already had an impact on the design of new quinolone antibacterials still in development (53). 

The term quinolone antibacterials describes a large group of drugs that are 4-quinolone derivatives with a... 

Fuhr U, Strobl G, Manaut F, Anders E-M, Sorgel F, Lopez-de-brinas E, et al. Quinolone antibacterial agents relationship between structure and in vitro inhibition of human cytochrome P450 isoform CYP1A2. Mol Pharmacol 1993 43 191-9. 

Bagchi, M. C., Mills, D., Basak, S. C. Quantitative structure-activity relationship (QSAR) studies of quinolone antibacterials against M. fortuitum and M. smegmatis using theoretical molecular descriptors. 

Zwitterionic character is notable in several therapeutic area series, e.g. in angiotensin-converhng enzyme inhibitors, quinolone anhbacterials and thrombin inhibitors. The aqueous solubiUty measurement of zwitterions is very pH dependent as might be expected. The relationship of aqueous solubiUty to ionization state is extraordinarily complex if the zwitterion is of the type capable of an equi-Ubrium between true zwitterion and formally neutral forms (e.g. as in a quinolone antibacterial). For these types of complex equilibria, salt effects on solubility may be unexpectedly large, e.g. solubility unexpectedly may track with the chaotropic character of the salt... 

The Jacobs-Gould intramolecular cyclization of diethyl N-(6-methyl-2-pyridyl)amino-methylenemalonate to 3-ethoxycarbonyl-7-methyl-l,8-naphthyrid-4-one is another reaction ideally suited to microwave heating, although conductively heated equipment was employed for laboratory-scale experiments [45]. The product is a key intermediate in the synthesis of nalidixic acid, the first of the quinolone antibacterials. The process usually is conducted at temperatures of 200-250 °C and in high dilution, with heat transfer oils such as the eutectic mixture of diphenyl ether and biphenyl. However, it proceeded rapidly, predictably and controllably under solvent-free conditions. 

Although there is versatility in the synthetic methodologies of each individual quinolone antibacterial, two different methods are utilized to synthesize the basic skeleton of l,4-dihydro-4-oxoquinoline-3-carboxylic acid. The first method is based on the Gould-Jacobs reaction [9] using appropriately substituted aniline derivatives and diethyl ethoxymalonate, which results in the formation of the intermediate anilinomethylenemalonate. Further thermal cyclization of this intermediate followed by hydrolysis gives rise to the targeted l,4-dihydro-4-oxoquinoline-3-carboxylic acid, according to Scheme 1. 

Syntheses of naphthyridone derivatives follow the same procedures as those of quinolones, except that substituted 2-aminopyridines (Gould-Jacobs modification) or substituted nicotinic ester/nicotinoyl chloride are used instead of anilines or o-halobenzoic acid derivatives. Most of the recently introduced quinolone antibacterials possess bicyclic or chiral amino moieties at the C-7 position, which result in the formation of enantiomeric mixtures. In general, one of the enantiomers is the active isomer, therefore the stereospecific synthesis and enantiomeric purity of these amino moieties before proceeding to the final step of nucleophilic substitution at the C-7 position of quinolone is of prime importance. The enantiomeric purity of other quinolones such as ofloxacin (a racemic mixture) plays a major role in the improvement of the antibacterial efficacy and pharmacokinetics of these enan-... 

According to molecular modeling studies, at the ground state the 6-lluoro analogue of 81 overlaps perfectly with the structure of norfloxacin (a well-established quinolone antibacterial agent) and is predicted to exhibit promising antibacterial activity. 

Further development in the chemistry of oxazolidinone antibacterials was based mainly on the assumption that the 4-pyridyl moiety of one of Dupont s lead compounds, E-3709, might be amenable to replacement by suitably saturated heterocyclic bioisosteres [48]. This assumption was based on an example in which successful replacement of the piperazine ring system in the quinolone antibacterials, such as ciprofloxacin, with a pyridine fragment, such as seen in Win-57273, results in improvement of both the antibacterial and the pharmacokinetic profiles of the compounds. Similarly, as in the case of ciprofloxacin and Win-57273, it was predicted that the presence of a small but highly electron-withdrawing fluorine atom would be tolerated at the meta position(s) of the central phenyl ring, and would confer enhanced antibacterial activity and/or other desirable properties to the targeted oxazolidinones, as shown in Fig. 3. 

Antibacterials. See Antibacterial agents Antibiotics Antimicrobials Quinolone antibacterials... 

Quinolone antibacterials, 21 215-235 economic aspects of, 21 231-232 mechanism of inhibition by, 21 216-221 modifiying, 21 222-223. structure-activity relationships in,... 

The synthesis and antibacterial properties of norfloxacin (2a) were described in 1980 [65]. In this key paper in the evolution of quinolone antibacterial agents, a series of 6,7,8-polysubstituted-l-ethyl-l,4-dihydro-4-oxoquinoline-3-carb-oxylic acids (13) was synthesized, employing previously developed quantitative structure-activity relationships (QSAR) for the corresponding 6-, 7- and 8-monosubstituted derivatives versus Escherichia coli. The QSAR analysis... 

Table 6.5. IN VITRO BIOLOGICAL PROPERTIES OF SEVERAL QUINOLONE ANTIBACTERIAL AGENTS [22]...

Quinolone (antibacterial) Oral Xanthotoxin (8-methoxypsoralen) Oral, ip, im... 

Thus quinolone antibacterial agents, such as ciprofloxacin CPFX 143 [201], ofloxacin OFLX144 [202],sparfloxacin SPFX145 [203] and trovaflaxin 146 [204] are members of a major class of antibacterial drugs. These fluoroquinolones show broad-spectrum antibacterial activity and are widely used to treat patients with infections, Eq. (58). 

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