以金黄色葡萄球菌转肽酶Sortase A 与底物LPXTG 的结合构象为模板，设计合成了12 个具有L-shape 构象的2- 苯基苯并呋喃-3- 酰胺衍生物作为Sortase A 抑制剂，并经核磁共振和高分辨质谱确认结构，其中10 个目标化合物未见文献报道。体外抑制活性结果显示，9 个目标化合物对Sortase A 具有较好的抑制活性[IC50=(22.2 ～ 62.3) μmol/L]。构效关系分析结果表明，苯并呋喃3- 位上的取代基为-CONHCH2CH(CH3)2 时抑制活性较好，而为-COOH 时则抑制活性丧失； 2- 位苄基上带有吸电子基如氰基时抑制活性较好，而为供电子基如羟基时抑制活性较差；苯并呋喃其他位置上的取代基对抑制活性未见明显影响。
Abstract
Based on the binding conformation of Staphylococcus aureus transpeptidase Sortase A and the substrate LPXTG as a template, twelve 2-phenyl-benzofuran-3-amide derivatives with L-shape conformation were designed and synthesized. The structures were confirmed by NMR and high-resolution mass spectrometry, and among them, ten target compounds had not been reported in the literature. Nine compounds showed excellent in vitro inhibitory activities on Sortase A[IC50=(22.2 - 62.3) μmol/L]. The structure-activity relationship analysis revealed that the inhibitory activity was better when -CONHCH2CH(CH3)2 at the 3-position of benzofuran, while the inhibitory activity was lost when -COOH at the same position, when the 2-position benzyl group had an electron withdrawing group such as cyano, the inhibitory activity was improved, compared with the electron donor group, such as -OH, the substituents at other positions of benzofuran had no significant effect on the inhibitory activity.
关键词
分选酶 A /
设计与合成 /
苯并呋喃衍生物 /
构效关系分析
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Key words
Sortase A /
design and synthesis /
benzofuran derivatives /
structure-activity relationship analysis
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参考文献
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