Quinolone generations

Quinolone-Gephalosporin Godrugs. Quinolones have been covalently linked to cephalosporins in order to generate a codmg containing one molecule of each type of antibacterial agent. An example is the fleroxacin—cefotaxime [63527-52-6] combination, Ro 23-9424 [115622-58-7] (23). 

The structure of the product of the Reimer-Tiemann reaction of 1,2,3-trimethylindole (24) has been confirmed as 3-dichloromethyl-1,3-dimethyl-2-methyleneindoline (25) by spectroscopy and oxidation to the iV -methyloxindole when the dichlorocarbene was generated under neutral conditions a ring-expanded product, 3-chloro-1,4-dimethyl-2-methylene-1,2-dihydroquinoline (26) could be isolated and oxidized to the corresponding a-quinolone. These reactions presumably proceed by mechanisms similar to those discussed for 2,3-di-... 

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). 

One frequently used method for synthesizing 2-quinolones is to react anilines with malonic esters. This reaction can be difficult to accomphsh by conventional methods [48,49] since high temperatures (250-350 °C) are required for the generation of an o -oxoketene intermediate 12 (Fig. 6). In a recent example of this type of reaction, Stadler et al. synthesized 4-hydroxyquinolin-2(lH)-ones by using a microwave-assisted procedure (Scheme 5) [50]. 

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). 

If one employs o-iodoaniline derivatives in this double insertion chemistry, 2-quinolones are generated in good yield after a basic work-up to remove the nitrogen protecting group (Scheme 14).15... 

A novel synthesis of iodothiazole 38 takes advantage of Wiemer s protocol for the synthesis of vinyl iodides from ketones <06JOC5031>. The thiazolyl phosphate 37, prepared from 2-isopropylaminothiazoline-4-one 36, is converted to the desired iodothiazole 38 upon treatment with in situ generated trimethylsilyl iodide. This iodide is a key intermediate in the synthesis of the quinolone substructure of the protease inhibitor BILN 2061. 

Since the introduction of nalidixic acid in 1963, structural modifications on the quinolones have been performed to improve either the antibacterial efficacy or pharmacokinetic/toxicologic profiles of these compounds. The newest quinolones possess broad-spectrum activity, favorable pharmacokinetic/toxicologic profiles, and potency against bacterial strains that are resistant to older generations of quinolones. This section describes the synthetic procedures for the new generation of quinolones that were studied during the 1995-2005 period. 

Reaction of these antibiotics with chlorine mostly generated chlorinated and OH-substituted by-products [86, 87]. Unlike fluroquinolones, whose quinolone ring is left mostly intact, disinfection with CIO2 may diminish the antibiotic capacity of tetracyclines because it leads to cleavage of the tetracyclines ring system [86,88]. On the other hand, oxidation of p-lactam antibiotics such as penicillin, amoxicillin, and cefadroxil with CIO2 leads to the formation of hydroquinone and a wide range of substituted phenols [89]. 

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. 

Cefalexin is a first-generation cephalosporin and therefore an alternative preparation would be Zinnat tablets, which contains cefuroxime, a second-generation cephalosporin. A penicillin such as Augmentin, which contains co-amoxiclav, can be an appropriate alternative since it provides a very similar spectrum of activity. Klaricid contains clarithromycin, which is a macrolide. Utinor contains norfloxacin, which is a quinolone that is effective in uncomplicated urinary-tract infections. Rocephin contains ceftriaxone, which is a third-generation cephalosporin that is available for parenteral administration only. 

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. 

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. 

Therapeutic uses of the quinolones include urinary and respiratory tract infections, GI and abdominal infections, STDs, and bone, joint, and soft tissue infections. Nalidixic acid is effective for urinary tract infections however, bacteria can become resistant, particularly if the drug is used for long periods. The second-generation fluoroquinolones are all equally efficacious in UTIs, and their activity is comparable to that of TMP-SMX. These drugs have shown efficacy in treating prostatitis and can serve as an alternative therapy for patients not responding to TMP-SMX. 

All quinolones interact with multivalent cations, forming chelation complexes resulting in reduced absorption. Major offenders are antacids vitamins containing calcium and iron can also be problematic. All fluoroquinolones interact with warfarin, didanosine (ddi), and phenytoin, resulting in decreased absorption or metabolism. Ciprofloxacin and other second-generation drugs interact with theophylline by decreasing its clearance, which leads to theophylline toxicity. 

With the advent of potent broad-spectrum antibiotics, such as the quinolones and third-generation cephalosporins, the indications for the use of the polymyxins, with their serious potential for toxicity, are few. Their only justifiable use may be as topical agents. 

Table 8.1 Miminal inhibitory concentrations (CMI in mg/L) of different generations of quinolones. ...

Third-generation quinolone >96% excreted unchanged (Stass and Kubitza, 1999). 

Quinolone Compounds More recent generation quinolones have dehber-ately been designed to have a higher retention and bioavaUabihty in the body (Jjemba and Robertson, 2006) but substantial amounts are still excreted as the parent compound. For example, more than 90% of trovafloxacin is excreted as parent compound (Stass and Kubitza, 1999). Furthermore, because of their more complex structure, these newer 4-quinolone antimicrobial agents are likely to be more persistent in the environment. The increased complexity of this group of antibiotics comes at an additional risk, that is, increased toxicity. Thus, some of them, after a brief period of use, have aheady been suspended, put under even more restricted use, or... 

One of the earlier second-generation quinolones indeed includes fluorine at the 6 position and a basic function at the 7 position, characteristic of the more potent drugs that also feature a broader spectmm of antibacterial activity. The starting material (39-3) for one of these agents is prepared by application of the same scheme as above to the substituted aniline (39-1). Nucleophilic aromatic displacement with A-methylpiperazine (39-4) proceeds at the 7 position due to activation by the carbonyl group para to the chlorine (39-5). Saponification of the displacement product leads to pefloxacin (39-6) [46]. 

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