title: Metronidazole containing pyrazole derivatives potently inhibit tyrosyl-tRNA synthetase: design, synthesis, and biological evaluation.
abstract: 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.
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China.
authors.forename: Long-Wang
authors.initials: LW
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China.
authors.forename: Peng-Fei
authors.initials: PF
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China.
authors.forename: Dan-Jie
authors.initials: DJ
authors.lastname: Tang
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China.
authors.forename: Xiang-Xiang
authors.initials: XX
authors.lastname: Tao
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China.
authors.forename: Ruo-Jun
authors.initials: RJ
authors.lastname: Man
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China.
authors.forename: Han-Yue
authors.initials: HY
authors.lastname: Qiu
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China. wangzhongchang2006@163.com.
authors.forename: Zhong-Chang
authors.initials: ZC
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China. xuchn@nju.edu.cn.
authors.forename: Chen
authors.initials: C
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China. zhuhl@nju.edu.cn.
authors.forename: Hai-Liang
authors.initials: HL
authors.lastname: Zhu
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001419:Bacteria / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D008795:Metronidazole / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D014448:Tyrosine-tRNA Ligase / Q000037:antagonists & inhibitors*
chemical_list: D000900:Anti-Bacterial Agents; D011720:Pyrazoles; D008795:Metronidazole; D014448:Tyrosine-tRNA Ligase
keywords: Pseudomonas aeruginosa; antibacterial agent; apoptosis; docking simulation; tyrosyl-tRNA synthetase