Synthesis and Antibacterial Activity of Some Novel 1-Substituted 1,4-Dihydro-4-oxo-7-pyridinyl-3-quinolinecarboxylic Acids. Potent Antistaphylococcal Agents

• Published in: Journal of medicinal chemistry Vol. 38; no. 14; pp. 2531 - 2540
• Main Authors: Reuman, Michael, Daum, Sol J, Singh, Baldev, Wentland, Mark P, Perni, Robert B, Pennock, Patrick, Carabateas, Philip M, Gruett, Monte D, Saindane, Manohar T, Dorff, Peter H, Coughlin, Susan A, Sedlock, David M, Rake, James B, Lesher, George Y
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 01.07.1995; Amer Chemical Soc
• Subjects: Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Bacillus - drug effects; Biological and medical sciences; Carboxylic Acids - chemical synthesis; Carboxylic Acids - chemistry; Carboxylic Acids - pharmacology; Chemistry, Medicinal; Enterococcus faecalis - drug effects; Life Sciences & Biomedicine; Medical sciences; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Pseudomonas aeruginosa - drug effects; Science & Technology; Staphylococcus aureus - drug effects; Streptococcus pneumoniae - drug effects; Structure-Activity Relationship; Staphylococcus aureus; INVITRO ACTIVITY; CROSS-COUPLING REACTION; BIOLOGICAL-ACTIVITY; WIN-57273; QUINOLONE ANTIMICROBIAL AGENTS; ANAEROBIC-BACTERIA; 1-ETHYL-7-<3-<(ETHYLAMINO)METHYL>-1-PYRROLIDINYL>-6,8-DIFLUORO-1,4-DIHYDRO-4-OX; FLUOROQUINOLONE; CIPROFLOXACIN; HYDROCHLORIDE; Nitrogen heterocycle; Enaminone; Quinoline derivatives; In vitro; Pyridine derivatives; Sensitivity resistance; Cyclization; Structure activity relation; Bicyclic compound; Bacteria; Micrococcales; Micrococcaceae; Aromatic compound; Ketoacid; Antibacterial agent; Chemical synthesis; Staphylococcus aureus
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00014a005

The palladium-catalyzed coupling of 3- and 4-(trialkylstannyl)pyridines with 7-bromo or 7-chloro 1-substituted 1,4-dihydro-4-oxo-3-quinalinecarboxylate 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 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 MIC(50) value for the most potent agents in this study against S. aureus ATCC 29213 is 0.008 mu g/mL. By comparison, ciprofloxacin and aminopyrrolidine 28 gave values of 0.25 and 0.015 mu g/mL, respectively, against this organism.