Compounds Lacking the c6 Fluorine

The ubiquitous C-6 fluorine, held constant for nearly two decades, has been successfully removed or replaced in a few more recent chemical series. The most advanced of these is T-3811 (Figure 9), currently in phase I clinical trials. T-3811, like the other third- and fourth-generation quinolones, exhibits Gram-positive activity improved over ciprofloxacin [154]. Its activity against penicillin-resistant S. pneumoniae is improved over that of trovafloxacin. Versus the Enterobacte-

figure 9 Selected earlier stage quinolone agents.

riaceae, T-3811 performs similarly to trovafloxacin, with activity against P aeruginosa somewhat less than that of ciprofloxacin. On the basis of the limited anaerobe MIC data available, T-3811 may fall into the fourth generation of quinolones, with potent activity against key pathogens [154].

Removal of the C-6 fluorine was found to be detrimental to activity if the C-8 position is unsubstituted. For compounds bearing an 8-OMe or 8-OCHF2, however, the importance of the 6-fluorine to antibacterial potency is decreased. Interestingly, in a closely related series, intravenous toxicity was decreased by removal of the 6-fluorine. T-3811 represents a departure from previously developed quinolones in additional structural aspects as well. Attachment of an aromatic group bonded directly to the C-7 carbon of the quinolone nucleus was utilized in rosoxacin in the 1970s, but compounds of this type have not progressed in a number of years. Other structural features of T-3811 were developed through toxicological examination. The 8-OCHF2 decreased convulsive activity on intrac-erebral injection compared to the 8-methoxy derivative, as did introduction of the methyl group on the C-7 sidechain. The regiochemistry and stereochemistry of the methyl group was chosen for maximum antibacterial activity [155].

A series of 6-amino derivatives has been described that retains Gram-positive and Gram-negative activity, albeit inferior to that of ciprofloxacin [156]. It was subsequently found, however, that addition of a methyl group at the 8-position served to enhance activity, and that use of a tetrahydroisoquinoline at the 7-position provided a compound (MF 5137, Figure 9) with Gram-positive activity superior to that of ciprofloxacin [157], and an MIC90 against S. pneumoniae eightfold lower than that of ciprofloxacin [158]. MF 5137 proved as efficacious as ciprofloxacin in an S. aureus septicemia mouse model on oral or subcutaneous administration [157].

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