Adenosine analogs as inhibitors of tyrosyl-tRNA synthetase: Design, synthesis and antibacterial evaluation

• Published in: Bioorganic & medicinal chemistry 2015-10, Vol.23 (20), p.6602-6611
• Main Authors: Wei, Wei, Shi, Wei-Kang, Wang, Peng-Fei, Zeng, Xiao-Tong, Li, Pan, Zhang, Ji-Rong, Li, Qian, Tang, Zhi-Ping, Peng, Jia, Wu, Lang-Zhou, Xie, Mei-Qun, Liu, Chan, Li, Xian-Hui, Wang, Ying-Chun, Xiao, Zhu-Ping, Zhu, Hai-Liang
• Format: Article
• Language: English
• Subjects: Adenosine - analogs & derivatives; Adenosine - chemistry; Adenosine - pharmacology; Adenosine analogs; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antibacterial; Dose-Response Relationship, Drug; Drug Design; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Escherichia coli - drug effects; Microbial Sensitivity Tests; Molecular docking; Molecular Dynamics Simulation; Molecular Structure; Pseudomonas aeruginosa - drug effects; Staphylococcus aureus - drug effects; Staphylococcus aureus - enzymology; Structure-Activity Relationship; Tyrosine-tRNA Ligase - antagonists & inhibitors; Tyrosine-tRNA Ligase - metabolism; Tyrosyl-tRNA synthetase inhibitors
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2015.09.018

[Display omitted] 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±0.07μM. 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.