Norfloxacin prodrugs

In attempts to improve the oral activity of norfloxacin, prodrug techniques have been employed. In an initial approach, the (5-methyl-2-oxo-l,3-diox-4-yl)-methyl group, which had been shown previously to be effective in a novel ampicillin prodrug, was investigated as a promoiety [ 109]. However, although the ester (77) liberates norfloxacin in the presence of mouse blood, after oral administration to mice, it was found that the blood levels of norfloxacin achieved are lower (approximately with respect to Cmax) than those achieved upon oral administration of an equimolar dose of norfloxacin, itself. This observation has been assumed to be due to an instability of this ester prior to absorption rather than an inability to liberate the parent drug after absorption. 

In contrast to other classes of antibiotics (aminoglucosides, P-lactams.. . ), most quinolones are well absorbed orally and only moderate efforts have been devoted to the design of prodrugs. All the reported chemistry was carried out by the team of Kanebo who tried to improve blood level and urinary recovery of norfloxacin [91, 92, 94, 95]. Compound 37, a N-masked norfloxacine prodrug liberated in vivo a high concentration of the parent compound after oral administration. In contrast, norfloxacin esters were poorly absorbed orally (Fig. 35). 

The related derivative (79), obtained by thermal rearrangement of the /V-oxide of (78), also exhibits excellent prodrug properties [110], This compound, when administered orally to mice, liberates excellent levels of norfloxacin and is slightly more effective in mouse protection tests than (78) and significantly better than norfloxacin. 

Table 6.29. COMPARISON OF THE ORAL EFFICACIES OF PRODRUG (80b) AND NORFLOXACIN IN MOUSE PROTECTION TESTS [111]...

The 3-formyl analogues of norfloxacin, pefloxacin and ciprofloxacin, (82a-c) have also been shown to function as prodrugs of their respective parent... 

For example this concept was applied to the synthesis of novel (acyloxyalkoxy) carbonyl bioreversible moieties for primary as well as secondary amines functions in drugs as illustrated with the case of a prodrug from the antibacterial Norfloxacin in scheme 135 (Ref. 194). 

Scheme 135 Preparation of a prodrug derived from Norfloxacin.

Synthesis and antimicrobial activity of 3-formyl analogs of norfloxacin, ciprofloxacin, and pefloxacin have been reported [93]. These studies have shown definitive evidence that the 3-formyl analogs of quinolones function as prodrugs and are oxidized in vivo to carboxylic acids. The higher bioavailability of formyl derivatives may be due to a change in physical and chemical properties by the lack of their amphoteric nature, compared to the parent zwitterionic compounds. 

E. Roseeuw, V. Coessens, A.-M. Balazuc, M. Lagranderie, P. Chavarot, A. Pessina, M.G. Neri, E. Schacht, G. Marchal, and D. Domurado, Synthesis, degradation, and antimicrobial properties of targeted macromolecular prodrugs of norfloxacin, Antimicrob. Agents Chemother, 47 (11), 3435-3441, 2003. 

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