New 1,4-dihydro[1,8]naphthyridine derivatives as DNA gyrase inhibitors.
Owing to the growing need for novel antibacterial agents, we synthesized a novel series of fluoroquinolones including 7-substituted-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylic acid derivatives, which were tested against clinically relevant Gram positive and Gram negative bacteria. Chemical structures of the synthesized compounds were identified using spectroscopic methods. In vitro antimicrobial effects of the compounds were determined via microdilution assay. Microbiological examination revealed that compounds 13 and 14 possess a good antibacterial profile. Compound 14 was the most active and showed an antibacterial profile comparable to that of the reference drugs trovafloxacin, moxifloxacin, and ciprofloxacin. A significant MIC90value (1.95μg/mL) against S. aureus ATCC 25923, E. coli ATCC 35218, and E. coli ATCC 25922 was recorded for compound 14. We observed reduced metabolic activity associated with compounds 13 and 14 in the relevant bacteria via a luminescence ATP assay. Results of this assay supported the antibacterial potency of compounds 13 and 14. An E. coli DNA gyrase inhibitory assay indicated that compound 14 is a potent inhibitor of E. coli DNA gyrase. Docking studies revealed that there is a strong interaction between compound 14 and the E. coli DNA gyrase enzyme. Genotoxicity and cytotoxicity evaluations of compounds 13 and 14 showed that compound 14 is non-genotoxic and less cytotoxic compared to the reference drugs (trovafloxacin, moxifloxacin, and ciprofloxacin), which increases its biological importance.
Anadolu University, Faculty of Pharmacy, Department of Pharmaceutical Microbiology, 26470 Eskişehir, Turkey. Electronic address: hulyakaraca@anadolu.edu.tr.
Hülya Karaca
HK
Gençer
Anadolu University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 26470 Eskişehir, Turkey; Anadolu University, Faculty of Pharmacy, Doping and Narcotic Compounds Analysis Laboratory, 26470 Eskişehir, Turkey.
Serkan
S
Levent
Anadolu University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 26470 Eskişehir, Turkey; Anadolu University, Faculty of Pharmacy, Doping and Narcotic Compounds Analysis Laboratory, 26470 Eskişehir, Turkey.
Ulviye
U
Acar Çevik
Anadolu University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 26470 Eskişehir, Turkey; Anadolu University, Faculty of Pharmacy, Doping and Narcotic Compounds Analysis Laboratory, 26470 Eskişehir, Turkey.
Yusuf
Y
Özkay
Anadolu University, Faculty of Pharmacy, Department of Pharmaceutical Toxicology, 26470 Eskişehir, Turkey.
Sinem
S
Ilgın
D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects; D027081:DNA Gyrase / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D009287:Naphthyridines / Q000737:chemistry / Q000494:pharmacology*
D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D009287:Naphthyridines; D027081:DNA Gyrase
ATP luminescence; Ames MPF; Antibacterial activity; DNA gyrase; Fluoroquinolones; NIH/3T3