title: 5-Amino-7-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-6,8-difluoro-1,4- dihydro-4-oxo-3-quinolinecarboxylic acid (PD 124,816). Synthesis and biological evaluation of a new class of quinolone antibacterials.
abstract: A series of 5-amino-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3- quinolinecarboxylic acids with piperazinyl or pyrrolidinyl side-chains appended at C7 were prepared to test the effect of the 5-amino group on the biological and physicochemical properties of these quinolones. The target compounds were synthesized from 2-nitro-3,4,5,6-tetrafluorobenzoic acid and were tested against a variety of Gram-negative and Gram-positive bacteria and the bacterial enzyme DNA gyrase, using standard microtitration techniques. The results are compared to reference quinolones such as ciprofloxacin. The 5-amino derivatives were significantly more potent (2-16 times) than their non-amino analogues. Alkylation or acylation of the 5-amino group reduced potency dramatically. The 5-amino group was neither basic nor nucleophilic. 5-Amino-7-(3-amino-1-pyrrolidinyl)-1-cyclopropyl- 6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (PD 124,816) was selected as the best compound in this study.
authors.affiliation: Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, MI 48105.
authors.forename: J M
authors.initials: JM
authors.lastname: Domagala
authors.forename: S E
authors.initials: SE
authors.lastname: Hagen
authors.forename: M P
authors.initials: MP
authors.lastname: Hutt
authors.forename: J P
authors.initials: JP
authors.lastname: Sanchez
authors.forename: J
authors.initials: J
authors.lastname: Sesnie
authors.forename: A K
authors.initials: AK
authors.lastname: Trehan
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis*; D000890:Anti-Infective Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D001419:Bacteria / Q000187:drug effects; D004927:Escherichia coli Infections / Q000188:drug therapy*; D024841:Fluoroquinolones; D007202:Indicators and Reagents; D051379:Mice; D008826:Microbial Sensitivity Tests; D015363:Quinolones / Q000138:chemical synthesis*; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents; D024841:Fluoroquinolones; D007202:Indicators and Reagents; D015363:Quinolones; C059082:PD 124816