Fluoronaphthyridines and -quinolones as antibacterial agents. 3. Synthesis and structure-activity relationships of new 1-(1,1-dimethyl-2-fluoroethyl), 1-[1-methyl-1-(fluoromethyl)-2-fluoroethyl], and 1-[1,1-(difluoromethyl)-2-fluoroethyl] substituted derivatives.
A series of novel N-1-(mono-,-(di- and -(trifluoro-tert-butyl)quinolones and -naphthyridines has been prepared. Structure-activity relationship (SAR) studies indicated that the in vitro antibacterial potency was the following order: 1-(1,1-dimethyl-2-fluoroethyl) greater than 1-[1-methyl-1-(fluoromethyl)-2-fluoroethyl] greater than 1-[1,1-(difluoromethyl)-2-fluoroethyl] substituents. In the quinolone series the monofluoro-tert-butyl derivatives were found to possess better in vitro antibacterial activity than the nonfluorinated-tert-butyl equivalents. In vivo PD50 values of the 1-fluoro-tert-butyl-substituted derivatives reflect pharmacokinetic behavior and incomplete oral absorption.
Remuzon
P
P
Centre de Recherche Bristol-Myers Squibb, Lognes, Marne-La-Vallee, France.
Bouzard
D
D
Cesare
P D
PD
Essiz
M
M
Jacquet
J P
JP
Kiechel
J R
JR
Ledoussal
B
B
Kessler
R E
RE
Fung-Tomc
J
J
D042462:4-Quinolones; D000818:Animals; D000890:Anti-Infective Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001419:Bacteria / Q000187:drug effects; D001424:Bacterial Infections / Q000188:drug therapy; D004285:Dogs; D007202:Indicators and Reagents; D051379:Mice; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009287:Naphthyridines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D013329:Structure-Activity Relationship
D042462:4-Quinolones; D000890:Anti-Infective Agents; D007202:Indicators and Reagents; D009287:Naphthyridines