New 8-(trifluoromethyl)-substituted quinolones. The benefits of the 8-fluoro group with reduced phototoxic risk.
A series of 8-(trifluoromethyl)-substituted quinolones has been prepared and evaluated for in vitro and in vivo antibacterial activity, and phototolerance in a mouse phototolerance assay. These analogues were compared to the corresponding series of 6,8-difluoro- and 6-fluoro-8H-quinolones (ciprofloxacin type). Although their in vitro antibacterial activities are less than the 6,8-difluoro analogues, the 8-(trifluoromethyl)quinolones are generally equivalent to their 8H analogues. In vivo, they are comparable to the 6,8-difluoro series and show up to 10-fold improvement in efficacy when compared to their ciprofloxacin counterparts vs Streptococcus pyogenes and Streptococcus pneumonia. In the phototolerance model, the 8-(trifluoromethyl)quinolones are comparable to the 8H-quinolones. Both of these series display much higher no effect doses (greater tolerance) than the corresponding 6,8-difluoroquinolones.
Sanchez
J P
JP
Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan 48106.
Bridges
A J
AJ
Bucsh
R
R
Domagala
J M
JM
Gogliotti
R D
RD
Hagen
S E
SE
Heifetz
C L
CL
Joannides
E T
ET
Sesnie
J C
JC
Shapiro
M A
MA
D042462:4-Quinolones; D000284:Administration, Oral; D000818:Animals; D000890:Anti-Infective Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity*; D001424:Bacterial Infections / Q000188:drug therapy; D005260:Female; D007279:Injections, Subcutaneous; D051379:Mice; D008826:Microbial Sensitivity Tests; D010787:Photosensitivity Disorders / Q000139:chemically induced*; D013329:Structure-Activity Relationship
D042462:4-Quinolones; D000890:Anti-Infective Agents