Metronidazole containing pyrazole derivatives potently inhibit tyrosyl-tRNA synthetase: design, synthesis, and biological evaluation

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• 作者：Long-Wang Chen ; Peng-Fei Wang ; Dan-Jie Tang ; Xiang-Xiang Tao ; Ruo-Jun Man ; Han-Yue Qiu ; Zhong-Chang Wang ; Chen Xu and Hai-Liang Zhu
• 刊名：Chemical Biology & Drug Design
• 出版年：2016
• 出版时间：October 2016
• 年：2016
• 卷：88
• 期：4
• 页码：592-598
• 全文大小：615K
• ISSN：1747-0285

文摘

As an important enzyme in bacterial protein biosynthesis, tyrosyl-tRNA synthetase (TyrRS) has been an absorbing therapeutic target for exploring novel antibacterial agents. A series of metronidazole-based antibacterial agents has been synthesized and identified as TyrRS inhibitors with low cytotoxicity and significant antibacterial activity, especially against Gram-negative organisms. Of the compounds obtained, 4f is the most potent agent which inhibited the growth of Pseudomonas aeruginosa ATCC 13525 (MIC = 0.98 μg/mL) and exhibited TryRS inhibitory activity (IC₅₀ = 0.92 μm). Docking simulation was performed to further understand its potency. Membrane-mediated apoptosis in P. aeruginosa was verified by flow cytometry.