7-Azetidinylquinolones as antibacterial agents. Synthesis and structure-activity relationships.
A series of novel antibacterial quinolones and naphthyridones has been prepared which contain 7-azetidinyl substituents in place of the usual piperazine or aminopyrrolidine groups. These azetidinyl derivatives were evaluated for in vitro activity by determining minimum inhibitory concentrations against a variety of bacteria. In vivo efficacy in the mouse infection model and blood levels in the mouse were determined for several compounds. The influence on the structure-activity relationships of varying substituents in the azetidine ring and at position 8 (CH, CF, CCl, N) and N-1 (ethyl, fluoroethyl, cyclopropyl, tert-butyl, 4-fluorophenyl, and 2,4-difluorophenyl) was also studied. Compounds with outstandingly broad-spectrum activity, particularly against Gram-positive organisms, improved in vivo efficacy, and high blood levels were identified in this work. 7-Azetidinyl-8-chloroquinolones were considered as warranting further development.
Frigola
J
J
Department of Medicinal Chemistry, Laboratories Dr. Esteve, Barcelona, Spain.
Parés
J
J
Corbera
J
J
Vañó
D
D
Mercè
R
R
Torrens
A
A
Más
J
J
Valentí
E
E
D042462:4-Quinolones; D000818:Animals; D000890:Anti-Infective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D001424:Bacterial Infections / Q000188:drug therapy; D051379:Mice; D008826:Microbial Sensitivity Tests; D009287:Naphthyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D013329:Structure-Activity Relationship
D042462:4-Quinolones; D000890:Anti-Infective Agents; D009287:Naphthyridines