Synthesis and antibacterial activity of novel and potent DNA gyrase inhibitors with azole ring

• Published in: Bioorganic & medicinal chemistry 2004-11, Vol.12 (21), p.5515-5524
• Main Authors: Tanitame, Akihiko, Oyamada, Yoshihiro, Ofuji, Keiko, Fujimoto, Mika, Suzuki, Kenji, Ueda, Tomohiko, Terauchi, Hideo, Kawasaki, Motoji, Nagai, Kazuo, Wachi, Masaaki, Yamagishi, Jun-ichi
• Format: Article
• Language: English
• Subjects: Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - pharmacology; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Azoles - chemical synthesis; Azoles - pharmacology; Biological and medical sciences; DNA Gyrase - metabolism; DNA gyrase inhibitor; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - pharmacology; Medical sciences; Microbial Sensitivity Tests - statistics & numerical data; Multidrug resistant strains; Pharmacology. Drug treatments; Pyrazole, oxazole and imidazole derivatives; Staphylococcus aureus - drug effects; Staphylococcus aureus - enzymology; Topoisomerase II Inhibitors
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2004.08.010

The pyrazole, oxazole and imidazole derivatives synthesized in this study exhibited potent antibacterial activity against multidrug resistant Gram-positive bacteria with minimal inhibitory concentration values equivalent to those against susceptible strains. The 4-piperidyl moiety and the pyrazole ring in 1-(3-chlorophenyl)-5-(4-phenoxyphenyl)-3-(4-piperidyl)pyrazole 2, which has previously shown improved DNA gyrase inhibition and target-related antibacterial activity, were transformed to other groups and the in vitro antibacterial activity of the synthesized compounds was evaluated. The selected pyrazole, oxazole and imidazole derivatives showed moderate inhibition against DNA gyrase and topoisomerase IV with similar IC 50 values (IC 50 = 9.4–25 μg/mL). In addition, many of the pyrazole, oxazole and imidazole derivatives synthesized in this study exhibited potent antibacterial activity against quinolone-resistant clinical isolates and coumarin-resistant laboratory isolates of Gram-positive bacteria with minimal inhibitory concentration values equivalent to those against susceptible strains.