Synthesis and antibacterial activity of novel 7-substituted-6-fluoro-1- fluoromethyl-4-oxo-4H-[1,3thiazeto[3,2-a]quinoline-3-carboxylic acid derivatives.
A series of 7-substituted-6-fluoro-1-fluoromethyl-4-oxo-4H- [1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid derivatives (2a-1) was prepared and evaluated for antibacterial activity. These compounds were obtained by deacylation of 4-benzoyloxy-2-(1-chloro-2-fluoroethyl)thio-6,7- difluoroquinoline-3-carboxylate (10) and subsequent intramolecular cyclization followed by substitution with cyclic amines and then hydrolysis. The intramolecular cyclization reaction of 18, one of the diastereomers (17, 18) revealed that the cyclization reaction proceeded through an inversion to afford (-)-11a in good chemical and optical yield. The enantiomers of 2a were prepared from the enantiomers of 11a, which were obtained by the optical resolution of the racemate using high-performance liquid chromatography (HPLC). Compounds 2a,b showed excellent in vitro and in vivo antibacterial activity against both gram-negative and gram-positive bacteria including quinolone and Methicillin-resistant Staphylococcus aureus.
Matsuoka
M
M
Research Laboratories, Nippon Shinyaku Co., Ltd., Kyoto, Japan.
Segawa
J
J
Amimoto
I
I
Masui
Y
Y
Tomii
Y
Y
Kitano
M
M
Kise
M
M
D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D002942:Circular Dichroism; D018360:Crystallography, X-Ray; D004927:Escherichia coli Infections / Q000188:drug therapy / Q000382:microbiology; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D008297:Male; D051379:Mice; D008826:Microbial Sensitivity Tests; D008968:Molecular Conformation; D011804:Quinolines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D013203:Staphylococcal Infections / Q000188:drug therapy / Q000382:microbiology
D000900:Anti-Bacterial Agents; D002264:Carboxylic Acids; D011804:Quinolines