Synthesis and antibacterial activity of some novel 1-substituted 1,4-dihydro-4-oxo-7-pyridinyl-3-quinolinecarboxylic acids. Potent antistaphylococcal agents.
The palladium-catalyzed coupling of 3- and 4-(trialkylstannyl)pyridines with 7-bromo or 7-chloro 1-substituted 1,4-dihydro-4-oxo-3-quinolinecarboxylates has provided access to the corresponding 1-substituted 1,4-dihydro-4-oxo-7-pyridinyl-3-quinolinecarboxylic acids. The antibacterial activity of these derivatives was studied with the finding that the optimal 1- and 7-position substituents for Gram positive activity are cyclopropyl and 4-(2,6-dimethylpyridinyl), respectively. We find that for the fluorine-substituted derivatives studied, the position of the fluorine on the quinolone nucleus or the number of fluorine atoms does not seem to be important for good Gram positive activity. For 1-cyclopropyl 7-(2,6-dimethyl-4-pyridinyl) derivatives, the 6-fluoro 4a, 8-fluoro 10d, 6,8-difluoro 10b, and 5,6,8-trifluoro 8, all provided equal antibacterial activity against Staphylococcus aureus ATCC 29213. There is also a correlation between the substitution on the 7-(4-pyridinyl) group and the Gram positive activity, particularly for S. aureus, clearly indicating that the 2,6-dimethylpyridinyl group is optimal. The MIC50 value for the most potent agents in this study against S. aureus ATCC 29213 is 0.008 microgram/mL. By comparison, ciprofloxacin and aminopyrrolidine 28 gave values of 0.25 and 0.015 microgram/mL, respectively, against this organism.
Reuman
M
M
Sterling Winthrop Inc., Collegeville, Pennsylvania 19426, USA.
Daum
S J
SJ
Singh
B
B
Wentland
M P
MP
Perni
R B
RB
Pennock
P
P
Carabateas
P M
PM
Gruett
M D
MD
Saindane
M T
MT
Dorff
P H
PH
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001407:Bacillus / Q000187:drug effects; D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013293:Enterococcus faecalis / Q000187:drug effects; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D013211:Staphylococcus aureus / Q000187:drug effects*; D013296:Streptococcus pneumoniae / Q000187:drug effects; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D002264:Carboxylic Acids