title: Tyrosyl-tRNA synthetase inhibitors as antibacterial agents: synthesis, molecular docking and structure-activity relationship analysis of 3-aryl-4-arylaminofuran-2(5H)-ones.
abstract: Thirty-five 3-aryl-4-arylaminofuran-2(5H)-one derivatives were designed, prepared and tested for their inhibitory activity against tyrosyl-tRNA synthetase. Out of these compounds, 3-(3-bromophenyl)-4-(3,5-dichlorophenylamino)furan-2(5H)-one (35) was the most active with IC(50) of 0.09 ± 0.02 μM. The structure-activity relationship revealed that introduction of chlorine atoms at both meta positions of aniline moiety significantly increased the enzyme inhibitory activity. The results of antibacterial assay revealed that the tested compounds showed good activity against Gram-positive bacteria, with 35 being the most potent with MIC(50) of 0.06 μg/mL against Staphylococcus aureus ATCC 25923. Molecular docking of 35 into S. aureus tyrosyl-tRNA synthetase active site was also performed. The inhibitor snugly fitting the active site may well explain its excellent inhibitory activity.
authors.affiliation: Key Laboratory of Plant Resources Conservation and Utilization, College of Hunan Province, Jishou University, Jishou 416000, PR China. xiaozhuping2005@163.com
authors.forename: Zhu-Ping
authors.initials: ZP
authors.lastname: Xiao
authors.forename: Tao-Wu
authors.initials: TW
authors.lastname: Ma
authors.forename: Mei-Lin
authors.initials: ML
authors.lastname: Liao
authors.forename: Yu-Ting
authors.initials: YT
authors.lastname: Feng
authors.forename: Xiao-Chun
authors.initials: XC
authors.lastname: Peng
authors.forename: Jia-Liang
authors.initials: JL
authors.lastname: Li
authors.forename: Zhi-Ping
authors.initials: ZP
authors.lastname: Li
authors.forename: Ying
authors.initials: Y
authors.lastname: Wu
authors.forename: Qun
authors.initials: Q
authors.lastname: Luo
authors.forename: Yang
authors.initials: Y
authors.lastname: Deng
authors.forename: Xiao
authors.initials: X
authors.lastname: Liang
authors.forename: Hai-Liang
authors.initials: HL
authors.lastname: Zhu
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D005663:Furans / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006094:Gram-Positive Bacteria / Q000187:drug effects* / Q000201:enzymology*; D016908:Gram-Positive Bacterial Infections / Q000188:drug therapy / Q000201:enzymology; D006801:Humans; D008958:Models, Molecular; D013203:Staphylococcal Infections / Q000188:drug therapy; 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; D005663:Furans; D014448:Tyrosine-tRNA Ligase