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-carboxylic acids possessing a [3-amino (or aminomethyl)-4-aryl (or cyclopropyl)-1-pyrrolidinyl] group at C-7 were synthesized and evaluated for their antimicrobial activity. The effect of the relative stereochemistry of the pyrrolidinyl substituents, as well as the presence of different functional groups on the 4-aryl (or cyclopropyl) moiety, was investigated in conjunction with their attachment to several quinolone or naphthyridone nuclei. In general, the incorporation of substituents on the aryl (or cyclopropyl) ring decreased in vitro and in vivo activity, regardless of the nature and relative position of the substituent. Bulky, 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 favorable than trans substitution. The majority of these effects were more apparent against the Enterobacteriaceae than against any other Gram-negative or Gram-positive organism and could be associated with negative interactions related to permeability or transport factors.