RESUMEN
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.
Asunto(s)
Antiinfecciosos/síntesis química , Inhibidores Enzimáticos/síntesis química , Furanos/química , Tirosina-ARNt Ligasa/antagonistas & inhibidores , Antiinfecciosos/química , Antiinfecciosos/farmacología , Sitios de Unión , Dominio Catalítico/efectos de los fármacos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Hongos/efectos de los fármacos , Furanos/síntesis química , Furanos/farmacología , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/enzimología , Relación Estructura-Actividad , Termodinámica , Tirosina-ARNt Ligasa/metabolismoRESUMEN
In a continuing study for discovering urease inhibitors based on flavonoids, nineteen reductive derivatives of flavonoids were synthesized and evaluated against Helicobacter pylori urease. Analysis of structure-activity relationship disclosed that 4-deoxy analogues are more potent than other reductive products. Out of them, 4',7,8-trihydroxyl-2-isoflavene (13) was found to be the most active with IC50 of 0.85 µM, being over 20-fold more potent than the commercial available urease inhibitor, acetohydroxamic acid (AHA). Kinetics study revealed that 13 is a competitive inhibitor of H. pylori urease with a Ki value of 0.641 µM, which is well matched with the results of molecular docking. Biological evaluation and mechanism study of 13 suggest that it is a good candidate for discovering novel anti-gastritis and anti-gastric ulcer agent.