Synthesis, and antibacterial activity of novel 4,5-dihydro-1H-pyrazole derivatives as DNA gyrase inhibitors

• Published in: Organic & biomolecular chemistry Vol. 12; no. 6; pp. 998 - 18
• Main Authors: Liu, Jia-Jia, Sun, Juan, Fang, Yun-Bin, Yang, Yong-An, Jiao, Rui-Hua, Zhu, Hai-Liang
• Format: Journal Article
• Language: English
• Published: CAMBRIDGE Royal Soc Chemistry 01.01.2014
• Subjects: Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Bacillus subtilis; Bacillus subtilis - drug effects; Bacillus subtilis - enzymology; Chemistry; Chemistry, Organic; DNA Gyrase - metabolism; Dose-Response Relationship, Drug; Escherichia; Escherichia coli - drug effects; Microbial Sensitivity Tests; Models, Molecular; Molecular Structure; Phenyl Ethers - chemical synthesis; Phenyl Ethers - chemistry; Phenyl Ethers - pharmacology; Physical Sciences; Pseudomonas aeruginosa; Pseudomonas aeruginosa - drug effects; Pyrazoles - chemical synthesis; Pyrazoles - chemistry; Pyrazoles - pharmacology; Science & Technology; Staphylococcus aureus; Staphylococcus aureus - drug effects; Staphylococcus aureus - enzymology; Structure-Activity Relationship; Topoisomerase II Inhibitors - chemical synthesis; Topoisomerase II Inhibitors - chemistry; Topoisomerase II Inhibitors - pharmacology; DESIGN; PYRAZOLE DERIVATIVES; ANALOGS; BIOLOGICAL EVALUATION; STAPHYLOCOCCUS-AUREUS; AGENTS; POTENT INHIBITORS; DISCOVERY
• ISSN: 1477-0520; 1477-0539
• DOI: 10.1039/c3ob41953c

A series of novel 4,5-dihydropyrazole derivatives ( 4a-4t ), containing the dinitrobenzotrifluoride moiety, as DNA gyrase inhibitors were designed and synthesized. Based on the preliminary results, compounds 4d , 4h and 4t with potent inhibitory activity in bacterial growth may be wonderful antibacterial agents; among them, compound 4t displayed the most potent activity with minimum inhibitory concentration (MIC) values of 3.125, 0.39, 0.39 and 0.39 μg mL −1 against Bacillus subtilis , Staphylococcus aureus , Pseudomonas aeruginosa , and Escherichia coli respectively, which was comparable with penicillin and kanamycin B with corresponding MIC values of 3.125, 3.125, 0.39, 0.39 μg mL −1 and 1.562, 1.562, 1.562, 1.562 μg mL −1 , respectively. In particular, compound 4d showed the most potent anti-Gram-positive bacterial activity with a MIC value of 0.39 μg mL −1 against the tested Gram-positive bacterial strains and exhibited the most potent B. subtilis DNA gyrase and S. aureus DNA gyrase inhibitory activity with an IC 50 of 0.125 μg mL −1 . Docking simulation was performed to insert compound 4d into the S. aureus DNA gyrase active site to determine the probable binding conformation. 4,5-dihydropyrazole derivatives containing dinitrobenzotrifluoride moiety as potential DNA gyrase inhibitors were designed and evaluated for their antibacterial and DNA gyrase inhibitory activities. Compound 4t was the most active antibacterial compound.