Synthesis and evaluation of adenosine containing 3-arylfuran-2(5H)-ones as tyrosyl-tRNA synthetase inhibitors

Wei Wei; Qi Liu; Zhen-Zhen Li; Wei-Kang Shi; Xing Fu; Jia Liu; Xuan Zhu; Xiao-Cong Wang; Ning Xu; Teng-Fei Li; Fu-Rui Jiang; Zhu-Ping Xiao; Hai-Liang Zhu

doi:10.1016/j.ejmech.2017.03.074

Synthesis and evaluation of adenosine containing 3-arylfuran-2(5H)-ones as tyrosyl-tRNA synthetase inhibitors

Eur J Med Chem. 2017 Jun 16:133:62-68. doi: 10.1016/j.ejmech.2017.03.074. Epub 2017 Mar 30.

Authors

Wei Wei¹, Qi Liu², Zhen-Zhen Li³, Wei-Kang Shi², Xing Fu², Jia Liu², Xuan Zhu², Xiao-Cong Wang², Ning Xu², Teng-Fei Li², Fu-Rui Jiang², Zhu-Ping Xiao⁴, Hai-Liang Zhu⁵

Affiliations

¹ College of Chemistry and Chemical Engineering, Hunan Engineering Laboratory for Analyse and Drugs Development of Ethnomedicine in Wuling Mountains, Jishou University, Jishou 416000, PR China; College of Chemistry and Chemical Engineering, Sichuan University of Arts and Science, Dazhou 635000, PR China.
² College of Chemistry and Chemical Engineering, Hunan Engineering Laboratory for Analyse and Drugs Development of Ethnomedicine in Wuling Mountains, Jishou University, Jishou 416000, PR China.
³ State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, PR China.
⁴ College of Chemistry and Chemical Engineering, Hunan Engineering Laboratory for Analyse and Drugs Development of Ethnomedicine in Wuling Mountains, Jishou University, Jishou 416000, PR China; State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, PR China. Electronic address: [email protected].
⁵ College of Chemistry and Chemical Engineering, Hunan Engineering Laboratory for Analyse and Drugs Development of Ethnomedicine in Wuling Mountains, Jishou University, Jishou 416000, PR China; State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, PR China. Electronic address: [email protected].

PMID: 28380394
DOI: 10.1016/j.ejmech.2017.03.074

Abstract

Tyrosyl-tRNA synthetase (TyrRS) is an aminoacyl-tRNA synthetase family protein that possesses an essential role in bacterial protein synthesis. The synthesis, structure-activity relationship, and evolution of a novel series of adenosine-containing 3-arylfuran-2(5H)-ones as TyrRS inhibitors are described. Advanced compound d3 from this series exhibited excellent affinity for TyrRS with IC₅₀ of 0.61 ± 0.04 μM. Bacterial growth inhibition assays demonstrated that d3 showed submicromolar antibacterial potency against Escherichia coli and Pseudomonas aeruginosa, and compared to the marketed antibiotics ciprofloxacin.

Keywords: 3-Arylfuran-2(5H)-one; Adenosine; Antibacterial; Molecular docking; Tyrosyl-tRNA synthetase inhibitors.

MeSH terms

Adenosine / analogs & derivatives*
Adenosine / chemical synthesis
Adenosine / pharmacology*
Anti-Bacterial Agents / chemical synthesis
Anti-Bacterial Agents / chemistry*
Anti-Bacterial Agents / pharmacology*
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology
Escherichia coli / drug effects
Escherichia coli / enzymology*
Escherichia coli Infections / drug therapy
HeLa Cells
Humans
Molecular Docking Simulation
Pseudomonas Infections / drug therapy
Pseudomonas aeruginosa / drug effects
Pseudomonas aeruginosa / enzymology*
Structure-Activity Relationship
Tyrosine-tRNA Ligase / antagonists & inhibitors*
Tyrosine-tRNA Ligase / metabolism

Substances

Anti-Bacterial Agents
Enzyme Inhibitors
Tyrosine-tRNA Ligase
Adenosine