Antibacterials quinolones

There are several methods of preparation of antibacterial quinolones, drugs widely used in the therapy of various bacterial diseases. The most general method is based on the nucleophilic cyclization of 2-halobenzoyl derivatives 402, leading to the key intermediates 403. The methodology is exemplified in Scheme 63 by the synthesis of a broad-spectrum drug ciprofloxacin... 

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). 

Mercury and nickel salts form many stable complexes with biologically important molecules such as those containing sulphydryl groups Chapter 5 stresses the importance and the dangers of these being formed in the skin from topical contact. The last 10 years have been a highly fertile and productive period in the discovery of antibacterial quinolones (reviewed in Chapter 6) which inhibit target enzymes at the molecular level. 

Perhydro derivatives of pyrido[l,2-6][l,2]oxazines are frequently applied in the total synthesis of various alkaloids to control the stereochemistry, and 4-(substituted amino)-5-fluoro-7-oxo derivatives of 3,7-dihydro-2//-pyrido[3,2,l-f7][2,l]benzoxazine- and l,2,3,7-tetrahydropyrido[3,2,l-//]cin-noline-8-carboxylic acids are considered as a subfamily of the third generation of antibacterial quinolones. 

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. 

Radi S, Bouzard D. Recent advances in the synthesis of antibacterial quinolones. Heterocycles, 1992, 34, 2143-2177. 

TABLE 8-6 Dissociation and isoelectric Constants for Antibacterial Quinolones ... 

The same scheme has been adopted for the determination of several antibacterials (quinolones and erythromycin A), fungicides, and parasiticides in salmon tissue. In this case, samples were extracted with acidic ACN, and then dSPE was carried out with a Bondesil NH2 sorbent, followed by LC-TOE-MS determination. Excellent recoveries were obtained with the exception of enrofloxacin (40%), although matrix suppression effects were observed for most of target compounds. ... 

On the basis of the study above and of some quite unexpected rises in drug levels and subsequent nephrotoxicity in a handful of patients taking the similarly metabolised immunosuppressant, ciclosporin, with a qui-nolone antibacterial (see Ciclosporin + Antibacterials Quinolones , p.1018), one review suggested that close monitoring would be appropriate if tacrolimus is given with any quinolone. However, in vitro studies have suggested that enoxacin does not affect the metabolism of tacrolimus, and ciprofloxacin does not affect the immunosuppressant activity of tacrolimus. Further study is needed. 

Microwave-A ctivated Solid Support Synthesis of New Antibacterial Quinolones... 

In this context, Kidwai et al. reported with the same method the synthesis of new antibacterial quinolones (60 Scheme 6.22) [61]. 

Das B, Madhusudhan P, Kashinatham A (2000) Microwave activated solid support synthesis of new antibacterial quinolones. Indian J Chem 39B 326-328... 

Vargas, F. and Rivas, C. 1997. Mechanistic studies on phototoxicity induced by antibacterial quinolones. 16 81—5. 

Vargas, E, Rivas, C., Diaz, Y. et al. 2003. Photoinduced interaction of antibacterial quinolones with human serum albumin. Toxicology Mechanisms and... 

For the synthesis of new-generation antibacterial quinolone carboxylic acids, reduction of a2aspiroketones by Phaeocrepsis sp. JCM 1880 afforded the corresponding (R)-alcohols in high ee as shown in Figure 11.10c [60,61]. 

Synthesis of an Intermediate for a New-Generation Antibacterial Quinolone For the synthesis of new-generation antibacterial quinolone carboxylic acids. 

SCHEME 33.9. Synthesis of intermediates for antibacterial quinolone by Phaeocrepsis sp. JCM 1880. 

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