Key Laboratory of Plant Resources Conservation and Utilization, College of Hunan Province, Jishou University, Jishou 416000, PR China.
Eur J Med Chem. 2011 Oct;46(10):4904-14. doi: 10.1016/j.ejmech.2011.07.047. Epub 2011 Aug 4.
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.
设计、合成并测试了 35 种 3-芳基-4-芳胺呋喃-2(5H)-酮衍生物，以评估它们对酪氨酰-tRNA 合成酶的抑制活性。在这些化合物中，3-(3-溴苯基)-4-(3,5-二氯苯基氨基)呋喃-2(5H)-酮（35）的活性最高，IC50 为 0.09±0.02μM。构效关系研究表明，苯胺部分的两个间位引入氯原子可显著提高酶抑制活性。抗菌活性测试结果表明，所测试的化合物对革兰氏阳性菌具有良好的活性，其中化合物 35 对金黄色葡萄球菌 ATCC 25923 的 MIC50 为 0.06μg/mL，活性最强。还对 35 与金黄色葡萄球菌酪氨酰-tRNA 合成酶活性位点进行了分子对接。抑制剂与活性位点的紧密结合可以很好地解释其优异的抑制活性。
