Enantiomers of 1-ethyl-7-[3-[(ethylamino)methyl]-1-pyrrolidinyl]-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid: preparation and biological activity

Journal of Medicinal Chemistry
1987.0

Abstract

We have recently reported the synthesis of a new quinolone antibacterial agent, l-ethyl-7-[3-[(ethylaminolmethyl]-1-pyrrolidinyl]-6,8-difluoro-1,4-dihydro-4-oxo-3 quinolinecarboxylic acid, CI-934 (1), which is unusually active against a wide spectrum of aerobic and anaerobic bacteria, especially against streptococcus and staphylococcus species, and is an effective inhibitor of bacterial gyrase. We have also demonstrated that this unique activity against the Gram-positive strains (streptococci and staphylococci) is directly related to the 3-(aminomethyl)pyrrolidinyl side chain 2. Virtually all of the significant quinolones reported to date either are achiral or are being developed as racemic mixtures. Recently, however, several cases have been reported in which the enantiomers of certain quinolones were separated, and a substantial difference in potency was observed between the chiral forms. In particular, flumequine (3), ofloxacin (4), and s-25930 (5) all have asymmetry at the methyl-substituted carbon in the benzoxazine or quinolizine rings. In all cases, most if not all of the activity (10-100-fold!) was present in just one enantiomer. Since fewer quinolones contain chiral side chains, much less has been reported on the influence of side-chain asymmetry on antibacterial activity. In just one case, the enantiomeric quinolones with 2-substituted pyrrolidinyl side chains were synthesized. Once again, one isomer (6) possessed a substantial share of the potency (10-60-fold). Because of the excellent antibacterial properties of 1 and the asymmetric center present in its N-ethyl-3-pyrrolidinemethanamine side chain, we report the synthesis and biological activity (in vivo, in vitro, and at the enzyme level) of the pure enantiomeric forms of this agent.

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