Quinolones systemic antibacterials

The first-generation and oldest quinolones exhibit limited gram-negative activity. Nalidixic acid and cinoxacin do not achieve systemic antibacterial levels and are thus restricted to therapy of bladder infections caused by urinary pathogens, such as E. coli and Klebsiella and Proteus spp. Although they are bactericidal agents, their use is restricted by resistance. 

Earlier quinolones such as nalidixic acid did not achieve systemic antibacterial levels and were useful only for treatment of lower urinary tract infections. Fluorinated derivatives (ciprofloxacin, levofloxacin, and others Figure 46-3 and Table 46-2) have greatly improved antibacterial activity compared with nalidixic acid and achieve bactericidal levels in blood and tissues. 

Abstract The data on 6-fluoro-l,4-dihydroquinolin-4-oxo-3-carboxylic acids and their structural analogues accumulated in the literature for the last 10-15 years are reviewed. Synthetic approaches to the quinolone system, as well as all kind of structural modifications by incorporating substituents into 1-8 positions or by means of annelation have been discussed. The structure-activity relationships for antibacterial fluoroquinolones, as well as the data on other types of biological activity for the family of bi- and polycyclic fluoroquinolones are presented. The formation of complexes of fluoroquinolones with metals and their applications have been considered. The bibliography - 377 references. 

More then a dozen representatives of the above ring systems were introduced into the human therapy. Actisomide (2) and trequinsin (3) are used as antiarrhytmic and antihypertensive agents, respectively. Sunepitron (4), a a 2-adrenoceptor antagonist, is under clinical trials for the treatment of anxiety and depression. Representatives of the third generation of antibacterial quinolone-3-carboxylic acids the blockbluster ofloxacin (5), its levorotatory enantiomer, levofloxacin (6), and rufloxacin (7) have gained wide acceptance for the treatment of bacterial infections of the respiratory and urinary tracts, skin, and soft tissues, as well as sexually transmitted diseases, and pazufloxacin (8) is under development. Praziquantel (9) is widely applied for the treatment of schistosomes- and cestode-caused infection in both veterinary and human therapies (Scheme 4). 

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. 

In summary, the adverse effects associated with the quinolones appear presently to be mild to moderate in severity and reversible upon discontinuation of therapy. Severe systemic adverse reactions are rare [62], It is suggested that the use of these agents should be avoided, as far as possible, in children and pregnant women and that caution be used in their administration to patients with a seizure disorder or those taking theophylline or warfarin [62]. Articles suggesting the appropriate clinical usage for these important antibacterials have appeared [64],... 

Antibacterial treatment is generally not required in cases of gastroenteritis. Typhoid fever is treated with ciprofloxacin (quinolone), cefotaxime (third generation cephalosporin) or chloramphenicol. Impetigo necessitates the systemic use of flucloxacillin or erythromycin. Topical fusidic acid or mupirocin may also be used. 

Like other aluminium salts, pulmonary aspiration of sucralfate can lead to acute lung injury. There is some systemic absorption of aluminium, which is probably significant only in patients with renal impairment. Administration can be associated with a degree of hypophosphataemia, and there is also interference with absorption of some other drugs, e.g. quinolone antibacterials, digoxin, quinidine, and warfarin. 

Nalidixic acid, the first antibacterial quinolone (Figure 46-3), was introduced in 1963. It is not fluorinated and is excreted too rapidly to be useful for systemic infections. Oxolinic acid and cinoxacin are similar in structure and function to nalidixic acid. Their mechanism of action is the same as that of the fluoroquinolones. These agents were useful only for the treatment of urinary tract infections and are rarely used now, having been made obsolete by the more efficacious fluorinated quinolones. 

Grohe K. The chemistry of the quinolones Methods of synthesizing the quinolone ring system. In Quinolone Antibacterials. Kuhlmann J, DalhoffA,... 

Simanjantuk, M.T., Sato, H., Tamai, I., Terasaki, T. and Tsuji, A. Transport of the new quinolone antibacterial agents of lomefloxacin and ofloxacin by rat erythrocytes and its relation to the nicotinic acid transport system. /. Pharmacobio-Dyn., 14, 475-481, 1991. 

Many quinoline derivatives are important biologically active agents. 8-Hydroxyquinoline and some of its halogenated derivatives are used as antiseptics. Chloroquine 111 is one of the older but still important antimalarials. A -Alkyl-4-quinolone-3-carboxylic acid and systems derived therefrom are constituents of antibacterials (gyrase inhibitors [112]) such as nalidixic acid 112, ciprofloxazin 113 and moxifloxazin 114. The quinoline-8-carboxylic acid derivative 115 (quinmerac) is employed as a herbicide for Galium aparine and other broad-leaved weeds. Methoxatin 116, known as coenzyme PQQ is a heterotricyclic mammalian cofactor for lysyl oxidase and dopamine P-hydroxylase [113]. 

Structure-activity relationships in both quinolone and naphthyridone series of compounds have shown that introduction of a C-6 substituent tends to enhance antibacterial activity [3, 5] and it is of particular interest that replacement of an hydrogen atom by an halogen atom especially fluorine results in an outstanding enhancement of the antibacterial activity. All the clinically useful new quinolones bear a fluorine at the C-6 position of the quinolone, naphthyridine, or benzoxazine ring system and consequently almost all the chemical modifications involved any position but C-6, the fluorine atom being always present. 

The majority of quinolones in clinical use belong to the subset of fluoroquinolones, which have a fluoro group attached to the central ring system. Among fluoroquinolones, there are molecules with one or two chiral centers. The position of a chiral center in relation to the quinolone ring influences antibacterial activity and pharmacokinetic parameters of isomers [4],... 

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