3-Aryl-4-acyloxyethoxyfuran-2(5H)-ones as inhibitors of tyrosyl-tRNA synthetase: Synthesis, molecular docking and antibacterial evaluation

• Published in: Bioorganic & medicinal chemistry 2013-09, Vol.21 (17), p.4914-4922
• Main Authors: Wang, Xu-Dong, Deng, Rui-Cheng, Dong, Jing-Jun, Peng, Zhi-Yun, Gao, Xiao-Ming, Li, Shu-Ting, Lin, Wan-Qiang, Lu, Chun-Lei, Xiao, Zhu-Ping, Zhu, Hai-Liang
• Format: Article
• Language: English
• Subjects: 3-Aryl-4-acyloxyethoxyfuran-2(5H)-ones; active sites; Anti-Infective Agents - chemical synthesis; Anti-Infective Agents - chemistry; Anti-Infective Agents - pharmacology; Antibacterial; antibacterial properties; bacteria; Binding Sites; Candida albicans; Catalytic Domain - drug effects; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Escherichia coli; fungi; Fungi - drug effects; Furans - chemical synthesis; Furans - chemistry; Furans - pharmacology; Gram-Negative Bacteria - drug effects; Gram-Positive Bacteria - drug effects; Microbial Sensitivity Tests; Molecular docking; Molecular Docking Simulation; Pseudomonas aeruginosa; Staphylococcus aureus; Staphylococcus aureus - drug effects; Staphylococcus aureus - enzymology; Structure-Activity Relationship; Thermodynamics; Tyrosine-tRNA Ligase - antagonists & inhibitors; Tyrosine-tRNA Ligase - metabolism; Tyrosyl-tRNA synthetase
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2013.06.066

Thirty-eight 3-aryl-4-acyloxyethoxyfuran-2(5H)-ones were designed, prepared and tested for antibacterial activities. 4-(2-(3-Chlorophenylformyloxy)ethoxy)-3-(4-chlorophenyl)furan-2(5H)-one (d40) showed the widest spectrum of activity with MIC50 of 2.0μg/mL against Staphylococcus aureus, 4.3μg/mL against Escherichia coli, 1.5μg/mL against Pseudomonas aeruginosa and 1.2μg/mL against Candida albicans. Thirty-eight 3-aryl-4-acyloxyethoxyfuran-2(5H)-ones were designed, prepared and tested for antibacterial activities. Some of them showed significant antibacterial activity against Gram-positive organism, Gram-negative organism and fungus. Out of these compounds, 4-(2-(3-chlorophenylformyloxy)ethoxy)-3-(4-chlorophenyl)furan-2(5H)-one (d40) showed the widest spectrum of activity with MIC50 of 2.0μg/mL against Staphylococcus aureus, 4.3μg/mL against Escherichia coli, 1.5μg/mL against Pseudomonas aeruginosa and 1.2μg/mL against Candida albicans. Our data disclosed that MIC50 values against whole cell bacteria are positive correlation with MIC50 values against tyrosyl-tRNA synthetase. Meanwhile, molecular docking of d40 into S. aureus tyrosyl-tRNA synthetase active site was also performed, and the inhibitor tightly fitting the active site might be an important reason why it has high antimicrobial activity.