ABSTRACT
3-Arylfuran-2(5H)-one derivatives show good antibacterial activity and were determined as tyrosyl-tRNA synthetase (TyrRS) inhibitors. In a systematic medicinal chemistry exploration, we demonstrated chemical opportunities to treat infections caused by Helicobacter pylori. Twenty 3-arylfuran-2(5H)-ones were synthesized and evaluated for anti-H. pylori, antioxidant and anti-urease activities which are closely interconnected with H. pylori infection. The results displayed that some of the compounds show excellent antioxidant activity, and good anti-H. pylori and urease inhibitory activities. Out of these compounds, 3-(3-methylphenyl)furan-2(5H)-one (b9) showed the most potent antioxidant activity (IC50=8.2 µM) and good anti-H. pylori activity (MIC50=2.6 µg/mL), and it can be used as a good candidate for discovering novel anti-gastric ulcer agent.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Ulcer Agents/chemical synthesis , Furans/chemistry , Anti-Bacterial Agents/metabolism , Anti-Bacterial Agents/pharmacology , Anti-Ulcer Agents/pharmacology , Anti-Ulcer Agents/therapeutic use , Antioxidants/chemistry , Binding Sites , Drug Evaluation, Preclinical , Furans/pharmacology , Furans/therapeutic use , Helicobacter pylori/drug effects , Helicobacter pylori/enzymology , Humans , Molecular Docking Simulation , Protein Structure, Tertiary , Stomach Ulcer/drug therapy , Tyrosine-tRNA Ligase/antagonists & inhibitors , Tyrosine-tRNA Ligase/metabolism , Urease/antagonists & inhibitors , Urease/metabolismABSTRACT
Tyrosyl-tRNA synthetase (TyrRS), an essential enzyme in bacterial protein biosynthesis, is an attractive therapeutic target for finding novel antibacterial agents, and a series of N2-(arylacetyl)glycinanilides has been herein synthesized and identified as TyrRS inhibitors. These efforts yielded several compounds, with IC50 in the low micromolar range against TyrRS from Staphylococcus aureus. Out of the obtained compounds, 3ap is the most active and exhibits excellent activity against both Gram-positive (S. aureus) and Gram-negative (Escherichia coli and Pseudomonas aeruginosa) bacterial strains. In comparison with the parent scaffold 3-arylfuran-2(5H)-one, N2-(arylacetyl)glycinanilide significantly improved the potency against Gram-negative bacterial strains, indicating that this scaffold offers a significant potential for developing new antibacterial drugs.