title: Synthesis and antibacterial activity of new quinolones containing a 7-[3-(1-amino-1-methylethyl)-1-pyrrolidinyl] moiety. Gram-positive agents with excellent oral activity and low side-effect potential.
abstract: A series of the R and S isomers of 7-[3-(1-amino-1-methylethyl)-1-pyrrolidinyl]-1,4-dihydro-4-oxoquinoline- and 1,8-naphthyridine-3-carboxylic acids was prepared to determine the effect on potency of the two methyl groups adjacent to the distal nitrogen in the pyrrolidinyl moiety. The antibacterial efficacy of these dimethylated derivatives was compared to the relevant 7-[3-(aminomethyl)-1-pyrrolidinyl] parent compounds and, to a lesser extent, the 7-[3-(1-aminoethyl)-1-pyrrolidinyl] analogues. The activity of the title and reference compounds was assayed in vitro using an array of Gram-negative and Gram-positive organisms and in vivo using a mouse infection model. Selected derivatives were then screened for potential side effects in a phototoxicity mouse model and an in vitro mammalian cell cytotoxicity protocol. The results showed that the R isomer displayed a 2-20-fold advantage in activity in vitro and a 2-15-fold advantage in vivo over the S isomer. Although equipotent to the 7-[3-(aminomethyl)-1-pyrrolidinyl] parent compounds in vitro, the R isomers of the 7-[3-(1-amino-1-methylethyl)-1-pyrrolidinyl] analogues showed a dramatic increase in in vivo potency, especially via the oral route of administration. These same R isomers also appeared to possess a reduced risk of phototoxicity and cytotoxicity. This combination of superior in vivo performance with a low degree of phototoxicity and mammalian cell cytotoxicity recommends these agents for further study. Of these agents, naphthyridine 16-R represents the optimal blend of potency and safety.
authors.affiliation: Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, Michigan 48105.
authors.forename: S E
authors.initials: SE
authors.lastname: Hagen
authors.forename: J M
authors.initials: JM
authors.lastname: Domagala
authors.forename: S J
authors.initials: SJ
authors.lastname: Gracheck
authors.forename: J A
authors.initials: JA
authors.lastname: Sesnie
authors.forename: M A
authors.initials: MA
authors.lastname: Stier
authors.forename: M J
authors.initials: MJ
authors.lastname: Suto
mesh_terms: D042462:4-Quinolones; D000284:Administration, Oral; D000818:Animals; D000890:Anti-Infective Agents / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000627:therapeutic use*; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D024841:Fluoroquinolones; D006090:Gram-Negative Bacteria / Q000187:drug effects*; D006094:Gram-Positive Bacteria / Q000187:drug effects*; D051379:Mice; D008826:Microbial Sensitivity Tests; D009287:Naphthyridines / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000627:therapeutic use*; D011759:Pyrrolidines / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000627:therapeutic use*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D042462:4-Quinolones; D000890:Anti-Infective Agents; D024841:Fluoroquinolones; D009287:Naphthyridines; D011759:Pyrrolidines; C085884:PD 138312