Ofloxacin

Another important development in the stmcture—activity relationships of quinolone antibacterials came with the introduction of the 1,8-bridged quinolone ofloxacin (6a). In this quinolone, the movement of the ethyl group at the 1-position is restricted by "tying" it to the 8-position in the form of a 1,4-benzoxazine ring. In vitro activity improvements are found that are more or less comparable to the improvements noted with ciprofloxacin (35,41—43). 

A variation on ofloxacin is mfloxacin (20) this compound lacks the methyl group on the 1,8-bridge and contains a sulfur in place of the oxygen attached to the 8-position. Rufloxacin, although less potent than ofloxacin, is well absorbed and has longer half life than does ofloxacin (44—46). 

When ofloxacin was first introduced it was made available as the racemate. Later the optical isomers were prepared and it was found that the (3)-enantiomer, DR 3355 (6b), was substantially more active (8—128-fold) than the (R)-isomer against a broad range of bacteria (47—50). This chiral preference is not unique to ofloxacin and has been demonstrated in other quinolones as well (51,52). This significant finding has already had an impact on the design of new quinolone antibacterials still in development (53). 

The 5-position of quinolones can be substituted by small groups such as halogens, hydroxyl, or amino (54—56). The amino group at this position can be advantageous, particularly when appHed to 6,8-difluoro-7-piperazinyl or 6,8-difluoro-7-pyrrohdinyl quinolones. In contrast to 6,8-difluoro quinolones, when this replacement is appHed to ofloxacin, the resulting derivative has reduced antibacterial activity (57). Replacement of the 5-amino group with methylamine or dimethylamine causes activity to drop substantially. Sparfloxacin [110871-86-8] (21), a representative of 5-amino-6,8-difluoro quinolones, affords modest improvements in gram-positive activity as well as increased in vivo potency when compared with both ciprofloxacin and ofloxacin (54). 

Eluoroquinolone antibiotic ofloxacin in therapy of mycobacterioses 97MI15. 

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). 

Aminoazetidin-2-ones were acylated with ofloxacin (5) by standard DCC-HOBT methodology (96MI14). 

Levofloxacin (6) was enantioselectively obtained by the enzymatic hydrolysis of ofloxacin butyl ester by immobilization of porcine liver esterase (01MI25, 01MI32). 

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]. 

Proteins (BSA or ovomucoid, OVM) have also been successful in the preparative resolution of enantiomers by liquid-liquid extraction, either between aqueous and lipophilic phases [181] or in aqueous two-phase systems (ATPS) [123, 180]. The resolution of d,l-kynurenine [180] and ofloxacin and carvediol [123] were performed using a countercurrent extraction process with eight separatory funnels. The significant number of stages needed for these complete resolutions in the mentioned references and others [123, 180, 189], can be overcome with more efficient techniques. Thus, the resolution of d,l-kynurenine performed by Sellergren et al. in 1988 by extraction experiments was improved with CCC technologies 10 years later [128]. 

The fluoroquinolones include ciprofloxacin (Cipro), enoxacin (Penetrex), gatifloxacin (Tequin), lome-floxacin (Maxaquin), moxifloxacin (Avelox), ofloxacin (Floxin), and sparfloxacin (Zagain). 

The fluoroquinolones are used in the treatment of infections caused by susceptible microorganisms. The fluoroquinolones are effective in the treatment of infections caused by gram-positive and gram-negative microorganisms. They are primarily used in the treatment of susceptible microorganisms in lower respiratory infections, infections of the skin, urinary tract infections, and sexually transmitted diseases. Ciprofloxacin, norfloxacin, and ofloxacin are available in ophthalmic forms for infections in the eyes. 

Ciprofloxacin, gatifloxacin, and ofloxacin are the only fluoroquinolones given intravenously (IV). None of the fluoroquinolones are given intramuscularly (IM). 

The ability of chitosan hydrochloride to enhance the transcorneal permeability of the drug has been demonstrated [289]. Polyethylene oxide (PEO) was used as a base material to which ofloxacin-containing chitosan microspheres prepared by spray-drying were added and powder compressed resulting in circular inserts (6 mm). 

Co-administration of ofloxacin and chitosan in eyedrops increased the bioavailabUity of the antibiotic [290]. Trimethyl chitosan was more effective because of its solubility (plain chitosan precipitates at the pH of the tear fluid). On the other hand, N-carboxymethyl chitosan did not enhance the corneal permeability nevertheless it mediated zero-order ofloxacin absorption, leading to a time-constant effective antibiotic concentration [291]. Also W,0-carboxymethyl chitosan is suitable as an excipient in ophthalmic formulations to improve the retention and the bioavailability of drugs such as pilocarpine, timolol maleate, neomycin sulfate, and ephedrine. Most of the drugs are sensitive to pH, and the composition should have an acidic pH, to enhance stability of the drug. The delivery should be made through an anion exchange resin that adjusts the pH at around 7 [292]. Chitosan solutions do not lend themselves to thermal sterilization. A chitosan suspension, however. 

C3H3CIO 78-95-5) see Befunolol Benfurodil hemisuccinate Benzarone Mexiletine Ofloxacin Secnidazole Sertaconazole Zoraepirac chloroacetonitrile... 

C6H3F2NO3 82419-26-9) see Levofloxacin Ofloxacin l-(23-dlfluoro-6-nitrophenoxy)-3 inethoxy-2-propanone (C,oH9F2N05 91040-35-6) see Levofloxacin l-(2 3-difluoro-6-nitrophenoxy)-2-propanone (CyH7F2N04 524y9-32-7) see Ofloxacin... 

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