Ofloxacin enantiomers

W]ith the development of synthesis methods via stereoselection and improvement in the analytical methods of optical isomers in the recent years, many came to believe that only one of the enantiomers is the important substance and that the other one is, if bluntly said, an almost impure substance. Influenced by ideas like these, we decided to focus on the antibacterial activity of the two [ofloxacin] enantiomers, resulting in the apphcation of optical resolution. 

Another example of the use ofHF-SLM separation concerns the resolution of racemic ofloxacin [200]. This important drug, a fluoroquinolone antibiotic with one chiral center, was separated in chiral systems by hoUow-fiber liquid-supported membrane technology combining with countercurrent fractional extraction. The two chiral solutions contained L-dibenzoyltartaric acid and D-dibenzoyltartaric acid in 1-octanol, and flowed through the lumen side and the sheU side of fibers, respectively. The solution which Uowed through the lumen side of fibers also contained racemic ofloxacin. The waU of hoUow fibers was fiUed with an aqueous of 0.1 mol/l Na2[ ll O4/[ fd O4 buffer solution of pH 6.86 containing 2 mmol/1 of cetyltrimethylammonium bromide for 48 h. The obtained optical purity for ofloxacin enantiomers was up to 90% when 11 hoUow-fiber membrane modules of 22 cm in length in series were used. 

Enantiomeric separation. Investigation of the absorption of ofloxacin enantiomers in vitro. 

Gascon, A.R. Campo, E. Hernandez, R.M. Calvo, B. Errasti, J. Pedraz Munoz, J.L. Pharmacokinetics of ofloxacin enantiomers after intravenous administration for antibiotic prophylaxis in biliary surgery. J. Clin. Pharmacol. 2000, 40, 869-874. 

TLC has been applied for the separation of ofloxacin enantiomers under conditions described below [11],... 

Under established conditions, good separation of ofloxacin enantiomers was achieved, the / f values were 0.46 and 0.54 and the selectivity factor was a =. 38. The authors revealed that separation of ofloxacin enantiomers may be carried out by use of 1% aqueous triethylammonium acetate at pH 4.1 without methanol. 

For the separation of ofloxacin enantiomers by TLC, some other stationary phases were used such as cellulose fra(4-methylbenzoate), cellulose tm(4-nitrobenzoate) [12], and cellulose (3,5-dinitrobenzoate) [13]. 

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). 

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). 

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]. 

Syntheses of naphthyridone derivatives follow the same procedures as those of quinolones, except that substituted 2-aminopyridines (Gould-Jacobs modification) or substituted nicotinic ester/nicotinoyl chloride are used instead of anilines or o-halobenzoic acid derivatives. Most of the recently introduced quinolone antibacterials possess bicyclic or chiral amino moieties at the C-7 position, which result in the formation of enantiomeric mixtures. In general, one of the enantiomers is the active isomer, therefore the stereospecific synthesis and enantiomeric purity of these amino moieties before proceeding to the final step of nucleophilic substitution at the C-7 position of quinolone is of prime importance. The enantiomeric purity of other quinolones such as ofloxacin (a racemic mixture) plays a major role in the improvement of the antibacterial efficacy and pharmacokinetics of these enan-... 

As is discussed at a later point in this review, it has been shown that the enantiomer (33) of ofloxacin [81] and the related enantiomer (34) of S-25930 [82] are each significantly more potent antibacterial agents than their respective enantiomers furthermore, the gem-dimethyl analogue (35) is as inactive as the... 

The enantiomers of the tricyclic quinolone ofloxacin and several structurally... 

Levofloxacin (1), the levo-isomer or the (5)-enantiomer of ofloxacin, received FDA approval in 1996 (Fish, 2003 Hurst et al., 2002 Mascaretti, 2003 Norrby, 1999 North et al., 1998). The initial approval covered community-acquired pneumonia, acute bacterial exacerbation of chronic bronchitis, acute maxillary sinusitis, uncomplicated skin and skin structure infections, acute pyelonephritis, and complicated urinary tract infections (North et al., 1998). Four years later, the levofloxacin indication list grew to include community-acquired pneumonia caused by penicillin-resistant Streptococcus pneumoniae. In addition, in 2002, nosocomial (hospital-acquired) pneumonia caused by methicillin-susceptible Staphylococcus aureus, Pseudomonas aeruginosa, Serratia marcescens, Haemophilus influenzae, Kliebsella pneumoniae, and Escherichia coli was added (Hurst et al., 2002). Finally in 2004, LVX was approved as a post-exposure treatment for individuals exposed to Bacillus anthracis, the microbe that causes anthrax, via inhalation (FDA, 2004). 

Levofloxacin, the (5)-enantiomer or (— )-enantiomer of ofloxacin, is approximately 8 to 128 times more potent than the racemic mixture thus it is believed that the... 

Before an asymmetric synthesis appeared of levofloxacin (1, (—)-ofloxacin), (—)- ofloxacin was isolated via optical, enzymatic, and crystallization resolution of the racemic ofloxacin (17) Drugs Future, 1992 Hayakawa et al., 1986, 1991). For instance, tricyclic core 52 was converted to ( + )-3,5-dinitrobenzoyl derivative 54 in 75% yield (Scheme 4.5). The enantiomers were then separated via high-performance liquid chromatography (HPLC) with a SUMIPAX OA-4200 column to deliver optically pure benzoyl esters 55a and 55b (Drugs Future, 1992 Hayakawa et al., 1986, 1991). 

To the Court this was an important admission as it rebutted an earlier assertion by the inventor s representatives that structure-activity relationship principles would have completely discouraged skilled artisans from preparing the separate isomers of the racemic mixture (ofloxacin) or from reasonably expecting that one enantiomer would exhibit greater activity than the racemic mixture. The publication also indicated that... 

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. 

Levofloxacin, the levorotatory (5)-enantiomer of the racemate ofloxacin, is an oral and parenteral fluoroquinolone that has bactericidal activity against a wide spectrum of Gram-negative and Gram-positive bacilli (including Streptococcus pneumoniae), as well as atypical respiratory pathogens. 

Because ofloxacin has an a.synimetric carbon atom in its structure, it is obtained and supplied commercially as a race-mate. The racemic mixture has been rc.solved, and (he enantiomers independently synihe.sized and evaluated for antibacterial activity. The 35(-) isomer is substantially more active (8 to 125 times, depending on the bacterial species) than the 3/f( -f) isomer and has recently been marketed as levofloxacin (Levaquin) for the same indications as the race-mate. 

Lehr, K.-H. Damm, P. Quantification of the enantiomers of ofloxacin in biological fluids by high-performance liquid chromatography. J.Chromatogn, 1988, 425, 153-161... 

Zeng, S. Zhang, L. Liu, Z.Q. [Quantification of the enantiomers of ofloxacin in human urine by RP-HPLC with chiral mobile phase additive]. Yao Hsueh Hsueh Poo, 1994, 29, 223-227 Israel, D. Gillum, G. TXirik, M. Harvey, K. Ford, J. Dalton, H. Towle, M. Echols, R. Heller, A.H. Polk, R. Pharmacokinetics and serum bactericidal titers of ciprofloxacin and ofloxacin following mul-... 

About at the same time, enantiomers of ofloxacin have been described and synthetized through optical resolution of a racemic intermediate of ofloxacin by high-pressure liquid chromatography [57]. 

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