2- Quinolones

Quinolones is the name given to a broad family of synthetic chemotherapeutic antibacterials chemically based on the 4-quinolone and 1,8-naphthyridine structures. The structures of these two quinolone nuclei and an example of a drug from each of these groups are shown in Fig. 6.17a, b. Cinoxacin is an example of a 

See Sect. 4.4 for a detailed discussion of drug challenge tests. 

There appears to be no delayed reactions to quinolone antibacterial drugs following challenge tests or skin tests. 

Direct IgE-binding activity of different analogues of pipemidic acid  

Pyrimidinyl- Acetopyrimidinyl- pipemidic acid piperazine piperazine 

Recent research on 4-quinolone-3-carboxylates has led to discovery of the fluoroquinolones, which are second-generation quinolones and include ciprofloxacin, danofloxacin, difloxacin, enrofloxacin, flumequine, marbofloxacin, norfloxacin, ofloxacin, and sarafloxacin. The main difference between classic quinolones and the fluoroquinolones is that the latter contain a fluorine atom at the C-3 position and a piperazinyl group at the C-7 position (Fig. 3.6). 

The addition of either the fluorine or the piperazino moiety, or both, to the basic quinolone backbone enhances the overall antibacterial activity of the new compounds. Fluorine increases the activity against gram-positive pathogens, 

The main application of fluoroquinolones has been for gastrointestinal and respiratory infections. The US Food and Dmg Administration has approved the therapeutic use of saratloxacin in poultry, making this the first approved fluroqui-nolone in food animals (137). Other members of this class of drugs have been petitioned for similar use. Although not approved for use in treatment of infections in cows, enrofloxacin is the most commonly used fluroquinolone in the European Union (138). 

Gastrointestinal disturbances including nausea, vomiting, and diarrhea are the most frequent adverse affects of quinolone antibiotics. Headache, visual disturbances, and insomnia have been reported. Rashes, pruritus and epidermal necrolysis have sometimes also occurred. Quinolones are not recommended for children, adolescents, and pregnant and breastfeeding women because they cause joint erosions in immature animals. 

As a rule, when quinolones are administered orally, their absorption from the gastrointestinal tract is rapid and almost complete, but food in the stomach delays their absorption. In unweaned calves, fluoroquinolones are often given in the milk replacer, but oral bioavailability is slightly reduced compared with the oral drench (139). On tire other hand, fermentation in the rumen of mature ruminants precludes the oral use of fluoroquinolones. Injectable solutions are also available for systemic therapy of large animals and turkeys. 

Quinolone carboxylic acids are a class of totally synthetic antibacterial agents which have the general structure (1). 

This representation is intended to encompass 4-oxo-3-quinolinecarboxyhc acids as well as the corresponding 1,8-naphthyridines, cinnolines, and pyrido[2,3- 55pyrimidines. These classes are illustrated by ciprofloxacin [85721-33-1] (2) (1), naUdixic acid [389-08-2] (3) (2), cinoxacin [28657-80-9] (4) (3), and piromidic acid [19562-30-2] (5) (4), respectively. 

Kirk-Othmer Encyclopedia of Chemical Technology (4th Edition) 

skin infections, upper and lower RTI, and GI tract infection 

The systematic names are as follows (2) l-Cyclopropyl-6- uoro-l,4-dihydro-4-oxo-7-(l-pipera2iQyl)-3-quiQolinecarboxyhc acid (7) l-ethyl-6- uoro-l,4-dihydro-4-oxo-7-(l-pipera2iQyl)-l,8-naphthyridine-3-carboxyhc acid (8) l-ethyl-6- uoro-l,4-dihydro-4-oxo-7-(l-pipera2iQyl)-3-quiQolinecarboxyhc acid (6a) 

Pefloxacin (33) is the N-methyl analogue of norfloxacin (58) and is at least partly converted to it by metabolic enzymes in vivo. It has been launched in France for the treatment of a number of infections including those caused by sensitive strains of Pseudomonas aeruginosa. It can be synthesized starting with the Gould-Jacobs reaction of 3-chloro-4-fluoroaniline (28) and diethyl ethoxymethylenemalonate in an addition-elimination sequence leading to 29 which undergoes 

Norfloxacin (41), the substance which triggered this avalanche of activity, has recently been introduced into clinical practice in the United States. Its synthesis parallels closely that of its N-methyl analogue, pefloxacin, except that the nucleophilic aromatic displacement reaction of 32 is carried out with mono-N-carboethoxypiperazine instead and the final step encompasses deblocking of this carbamoyl ester moiety [8]. 

The generally accepted structure-activity relationships developed in the early work in the quinolone series held that the N-1 substituent needed to be small and aliphatic. This picture was upset in a dramatic way with the discovery of the excellent potency and antimicrobial spectrum of difloxacin (45) and its congeners in which the substituent on N-1 is an aromatic ring. The synthe- 

Alternately, amifloxacin can be prepared via the ofloxacin/difloxacin route using an addition-elimination reaction with unsymmetiical N-methyl-N-formyl hydrazone to give 49 [14]. 

Most of the widely used antidepressants are tricyclics related to imipramine. A 1-phenyltetrahy-droisoquinoline analogue, nomifensine (60), departs from this structural pattern. Hiarmacologi-cally it inhibits the reuptake of catecholamines such as dopamine at neurons. It can be synthesized by alkylation of 2-nitrobenzyl-methylamine with phenacyl bromide followed by catalytic reduction of the nitro group (Pd-C) and then hydride reduction of the keto moiety to give 59. Strong acid treatment leads to cyclodehydration to nomifensine (60) [17]. 

Enterococcus faecalis, Straphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes 

Enterobacter cloacae, Escherichia coli, Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, Legionella pneumophila, Moraxella catarrhalis, Proteus mirabilis. Pseudomonas aeruginosa 

Staphylococcus epidermidis. Streptococcus (Group C/F), Streptococcus (Group G), Staphylococcus saprophyticus, Streptococcus agalactiae, Viridans group streptococci 

400 mg every 12 hours for severe urinary tract infections 

Variable effect on renal function and cyclosporine metabolism. Monitor cyclosporine levels and renal function carefully 

2-methylbutyl]4,5-dihydro-l, 3-thiazole-5 -carbonyl] amino] -4-methylpentanoyl] amino] -5-[[(25 )-l-[[(3N,6R,9N, 12R, 155, 18R,215)-3-(2-amino-2-oxoethyl)- 8-(3-aminopropyl)-15-butan-2-yl-6-(carboxymethyl)-9-(3//-imidazol-4-ybnethyl)-2,5,8,ll,14,17,20-heptaoxo-12-(phenylmethyl)-l,4,7,10,13, 

19-heptazacyclopentacos-21-yl] amino] -3 -methyl-1 -oxopentan-2-yl]amino]-5-oxopentanoic acid 

0X0-1 -[[6,9,18-tris(2-aminoethyl)-15 -benzyl-3 -(1 -hydroxyethyl)-12-(2-methylpropyl)-2,5,8,l 1,14,17,20-heptaoxo-1,4,7,10,13,16,19-heptazacyclotricos-21 -yl]amino]butan-2-yl]amino]-3-hydroxy-1 -oxobutan-2-yl] amino] -1 -oxobutan-2-yl] -6-methyloctanamide 

Ristomycin A 34-0-[2-(acetylamino)-2-deoxy- 3-D-glucopyranosyl] -22,31 -dichloro-7-demethyl-64-0 -demethyl-19-deoxy-56-0-[2-deoxy-2-[(8-methyl-l-oxononyl)amino]- 3-D-glucopyranosyl] -42-O-a-D-mannopyranosyl 

C88H95CI2N9O33 (teicoplanin A2 — 1) C88H97CI2N9O33 (teicoplanin A2—2) C88H97CI2N9O33 (teicoplanin A2—3) C89H99CI2N9O33 (teicoplanin A2—4) 

---

Recently kinetic data have become available for the nitration in sulphuric acid of some of these hydroxy compounds (table 10.3). For 4-hydroxyquinoline and 4-methoxyquinoline the results verify the early conclusions regarding the nature of the substrate being nitrated in sulphuric acid. Plots of log Q against — (Lf + logioflHao) fo " these compounds and for i-methyl-4-quinolone have slopes of i-o, i-o and 0-97 at 25 C respectively, in accord with nitration via the majority species ( 8.2) which is in each case the corresponding cation of the type (iv). At a given acidity the similarity of the observed second-order rate constants for the nitrations of the quinolones and 4-methoxy-quinoline at 25 °C supports the view that similarly constructed cations are involved. Application of the encounter criterion eliminates the possibilities of a... 

The case of i-methyl-4-quinolone is puzzling. The large proportion of the 3-nitro isomer formed in the nitration (table 10.3 cf. 4-hydroxyquinoline) might be a result of nitration via the free base but this is not substantiated by the acidity dependence of the rate of nitration or by the Arrhenius parameters. From r-methyl-4-quinolone the total yield of nitro-compounds was not high (table ro.3). 

ANTIBACTERIALAGENTSSYNTTiETIC - QUINOLONES] (Vol2) Cinnomomum camphora T. Nees Eberneier... 

---