Studies on pyridonecarboxylic acids. 1. Synthesis and antibacterial evaluation of 7-substituted-6-halo-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3- carboxylic acids.
A series of [1,3]thiazeto[3,2-a]quinoline-3-carboxylic acids and their esters were prepared and evaluated for antibacterial activity. The derivatives with a hydrogen or methyl group at C-1, fluorine at C-6, and piperazinyl or 4-methyl-1-piperazinyl group at C-7 showed superior in vitro antibacterial activity, and the derivatives with 4-methyl-1-piperazinyl group at C-7 had potent in vivo activity. Compound 29a (NM394) showed excellent in vitro antibacterial activity and low toxicity but poor absorption from the gastrointestinal tract. Compound 29ee (NM441), an N-[(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl] derivative of 29a, was found to possess a favorable pharmacokinetic profile and oral activity superior to that of ciprofloxacin in experimental animals.
Segawa
J
J
Research Laboratories, Nippon Shinyaku Company, Ltd., Kyoto, Japan.
Kitano
M
M
Kazuno
K
K
Matsuoka
M
M
Shirahase
I
I
Ozaki
M
M
Matsuda
M
M
Tomii
Y
Y
Kise
M
M
D000284:Administration, Oral; D000818:Animals; D000890:Anti-Infective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D004927:Escherichia coli Infections / Q000188:drug therapy; D024841:Fluoroquinolones; D008297:Male; D051379:Mice; D008826:Microbial Sensitivity Tests; D011552:Pseudomonas Infections / Q000188:drug therapy; D015363:Quinolones / Q000138:chemical synthesis*; D013329:Structure-Activity Relationship
D000890:Anti-Infective Agents; D002264:Carboxylic Acids; D024841:Fluoroquinolones; D015363:Quinolones