title: Adenosine analogs as inhibitors of tyrosyl-tRNA synthetase: Design, synthesis and antibacterial evaluation.
abstract: Herein we describe the synthesis and evaluation of a series of adenosine analogs for in vitro antibacterial activity against Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa. Out of these compounds, compound c6 has much stronger antibacterial potency against Pseudomonas aeruginosa than ciprofloxacin, and was determined to target tyrosyl-tRNA synthetase with IC50 of 0.8±0.07 μM. Structure-activity relationship analysis suggested that introduction of a fluorine atom at the 3'-position of benzene ring of the phenylacetyl moiety significantly increased affinities to the enzyme. In comparison with isopropylidene analogs, 2',3'-deprotected compounds displayed higher inhibitory activity. Molecular dockings provided an explanation for observations in biological assays.
authors.affiliation: College of Chemistry and Chemical Engineering, Jishou University, Jishou 416000, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wei
authors.affiliation: College of Chemistry and Chemical Engineering, Jishou University, Jishou 416000, PR China.
authors.forename: Wei-Kang
authors.initials: WK
authors.lastname: Shi
authors.affiliation: School of Medicine, Jishou University, Jishou 416000, PR China.
authors.forename: Peng-Fei
authors.initials: PF
authors.lastname: Wang
authors.affiliation: College of Chemistry and Chemical Engineering, Jishou University, Jishou 416000, PR China.
authors.forename: Xiao-Tong
authors.initials: XT
authors.lastname: Zeng
authors.affiliation: College of Chemistry and Chemical Engineering, Jishou University, Jishou 416000, PR China.
authors.forename: Pan
authors.initials: P
authors.lastname: Li
authors.affiliation: College of Chemistry and Chemical Engineering, Jishou University, Jishou 416000, PR China.
authors.forename: Ji-Rong
authors.initials: JR
authors.lastname: Zhang
authors.affiliation: College of Chemistry and Chemical Engineering, Jishou University, Jishou 416000, PR China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Li
authors.affiliation: College of Chemistry and Chemical Engineering, Jishou University, Jishou 416000, PR China.
authors.forename: Zhi-Ping
authors.initials: ZP
authors.lastname: Tang
authors.affiliation: College of Chemistry and Chemical Engineering, Jishou University, Jishou 416000, PR China.
authors.forename: Jia
authors.initials: J
authors.lastname: Peng
authors.affiliation: College of Chemistry and Chemical Engineering, Jishou University, Jishou 416000, PR China.
authors.forename: Lang-Zhou
authors.initials: LZ
authors.lastname: Wu
authors.affiliation: College of Chemistry and Chemical Engineering, Jishou University, Jishou 416000, PR China.
authors.forename: Mei-Qun
authors.initials: MQ
authors.lastname: Xie
authors.affiliation: College of Chemistry and Chemical Engineering, Jishou University, Jishou 416000, PR China.
authors.forename: Chan
authors.initials: C
authors.lastname: Liu
authors.affiliation: School of Medicine, Jishou University, Jishou 416000, PR China.
authors.forename: Xian-Hui
authors.initials: XH
authors.lastname: Li
authors.affiliation: College of Chemistry and Chemical Engineering, Jishou University, Jishou 416000, PR China.
authors.forename: Ying-Chun
authors.initials: YC
authors.lastname: Wang
authors.affiliation: College of Chemistry and Chemical Engineering, Jishou University, Jishou 416000, PR China; State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, PR China. Electronic address: xiaozhuping2005@163.com.
authors.forename: Zhu-Ping
authors.initials: ZP
authors.lastname: Xiao
authors.affiliation: College of Chemistry and Chemical Engineering, Jishou University, Jishou 416000, PR China; State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, PR China. Electronic address: zhuhl@nju.edu.cn.
authors.forename: Hai-Liang
authors.initials: HL
authors.lastname: Zhu
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004926:Escherichia coli / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D013211:Staphylococcus aureus / Q000187:drug effects / Q000201:enzymology; D013329:Structure-Activity Relationship; D014448:Tyrosine-tRNA Ligase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D014448:Tyrosine-tRNA Ligase; D000241:Adenosine
keywords: Adenosine analogs; Antibacterial; Molecular docking; Tyrosyl-tRNA synthetase inhibitors