Quinolone second-generation

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). 

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. 

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. 

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]. 

E coli, Klebsiella, Proteus Cephalosporin (first- or second- generation),2 TMP-SMZ1 Quinolone,3 aminoglycoside5... 

In the early 1980s, fluorinated quinolone antibactenals were discovered to possess better activity and PK properties (longer half lives and better oral efficacy). These so-called second-generation quinolone antibacterials are exemplified by norfloxacin (10),... 

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). 

Quinolone carboxylic acid antibacterials are synthetic compounds whose basic nuclear structure includes a quinolone ring and a carboxylic acid group. Fluoroquinolones are second-generation quinolones that contain in their molecule a fluorine and a piperazine ring. Quinolones are amphoteric compounds slightly soluble in polar solvents such as water, and insoluble in nonpolar solvents such as benzene and hexane. Most of these drugs are fluorescent and are quite stable in aqueous solution toward light, except miloxacin, which is reported to be unstable. 

E coli, klebsiella, proteus Cephalosporin (first- or second-generation), TMP-SMZ Quinolone, aminoglycoside... 

The breakthrough in the development of quinolones came with the appearance of norfloxacin 6 [19], a second-generation quinolone which combined a 6-fluorine substituent with a piperazine ring in the 7-position of the basic compound. Additional quinolones then followed in rapid succession pefloxacin [20], enoxacin [21] and fleroxacin [22] (Fig. 14.5). Particular mention must be made of ciprofloxacin 8 [23-25], ofloxacin 5 [26,27] and its active enantiomer levofloxacin 7 [28]. These quinolones have a broad spectrum of activity, which also includes Gram-positive bacteria and Pseudomonas aeruginosa, as well as favorable pharmacokinetics. The rapid absorption of these compounds from the gastrointestinal tract and their effective tissue penetration also allows them to be used for the treatment of systemic infections. 

As far as synthetic agents were concerned, isoniazid (a pyridine hydrazide structure) was found to be effective against human tuberculosis in 1952, and in 1962 nalidixic acid (Fig. 10.74) (the first of the quinolone antibacterial agents) was discovered. A second generation of this class of drugs was introduced in 1987 with ciprofloxacin (Fig. 10.74). 

Fierens, C. Hillaert, S. Van den Bossche, W. The qualitative and quantitative determination of quinolones of first and second generation by capillary electrophoresis. J. Pharm. Biomed. Anal. 2000, 22, 763 772. 

Moraxella (Branhamella) catarrhalis TMP-SMZ,1 cephalosporin (second- or third- generation)2 Quinolone,3 macrolide4... 

Quinolones are divided into "generations" based on their spectrum of activity. The higher the generation, the broader the spectrum of activity. First generation UTIs Second and third generations UTIs, prostatitis, respiratory tract infections, sinusitis, infectious diarrhea, uncomplicated skin and skin structure infections, traveler s diarrhea... 

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