Tyrosyl-tRNA synthetase inhibitors as antibacterial agents: Synthesis, molecular docking and structure–activity relationship analysis of 3-aryl-4-arylaminofuran-2(5H)-ones

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 IC50 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 MIC50 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.

3-(3-Bromophenyl)-4-(3,5-dichlorophenylamino)furan-2(5H)-one (35) is a potent tyrosyl-tRNA synthetase inhibitor with IC50 of 0.09 ± 0.02 μM, and showed excellent antibacterial activity against Staphyloccocus aureus with MIC50 value of 0.06 μg/mL.Figure optionsDownload as PowerPoint slideHighlights
► Thirty-five furan-2(5H)-ones were determined as tyrosyl-tRNA synthetase inhibitors.
► The most potent inhibitor showed MIC50 18-fold lower than that of kanamycin.
► Docking model of the most potent inhibitor could well explain its excellent activity.