SYNTHESIS AND ANTIMICROBIAL EVALUATION OF A SERIES OF 7-[3-AMINO (OR AMINOMETHYL)-4-ARYL (OR CYCLOPROPYL)-1-PYRROLIDINYL]-4-QUINOLONE- AND -1,8-NAPHTHYRIDONE-3-CARBOXYLIC ACIDS

A series of 6-fluoroquinolone- and 6-fluoro-1,8-naphthyridone-3-carbox ylic acids possessing a [3-amino (or aminomethyl)-4-aryl (or cycloprop yl)-1-pyrrolidinyl] group at C-7 were synthesized and evaluated for th eir antimicrobial activity. The effect of the relative stereochemistry of the pyrrolidinyl substituents, as well as the presence of differen t functional groups on the 4-aryl (or cyclopropyl) moiety, was investi gated in conjunction with their attachment to several quinolone or nap hthyridone nuclei. In general, the incorporation of substituents on th e aryl (or cyclopropyl) ring decreased in vitro and in vivo activity, regardless of the nature and relative position of the substituent. Bul ky, lipophilic groups and substitution at the 2- and 3-position of the aromatic ring were particularly deleterious. Within a limited subset of derivatives, cis substitution of the pyrrolidine ring was less favo rable than trans substitution. The majority of these effects were more apparent against the Enterobacteriaceae than against any other Gram-n egative or Gram-positive organism and could be associated with negativ e interactions related to permeability or transport factors.