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N-Leucinyl Benzenesulfonamides as Structurally Simplified Leucyl-tRNA Synthetase Inhibitors
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2018-01-23 00:00:00 , DOI: 10.1021/acsmedchemlett.7b00374 Michael H. Charlton 1 , Rihards Aleksis 2 , Adélaïde Saint-Leger 3, 4 , Arya Gupta 5 , Einars Loza 2 , Lluís Ribas de Pouplana 3, 4 , Ilze Kaula 2 , Daina Gustina 2 , Marina Madre 2 , Daina Lola 2 , Kristaps Jaudzems 2 , Grace Edmund 1 , Christopher P. Randall 5 , Louise Kime 5 , Alex J. O’Neill 5 , Wil Goessens 6 , Aigars Jirgensons 2 , Paul W. Finn 1, 7
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2018-01-23 00:00:00 , DOI: 10.1021/acsmedchemlett.7b00374 Michael H. Charlton 1 , Rihards Aleksis 2 , Adélaïde Saint-Leger 3, 4 , Arya Gupta 5 , Einars Loza 2 , Lluís Ribas de Pouplana 3, 4 , Ilze Kaula 2 , Daina Gustina 2 , Marina Madre 2 , Daina Lola 2 , Kristaps Jaudzems 2 , Grace Edmund 1 , Christopher P. Randall 5 , Louise Kime 5 , Alex J. O’Neill 5 , Wil Goessens 6 , Aigars Jirgensons 2 , Paul W. Finn 1, 7
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N-Leucinyl benzenesulfonamides have been discovered as a novel class of potent inhibitors of E. coli leucyl-tRNA synthetase. The binding of inhibitors to the enzyme was measured by using isothermal titration calorimetry. This provided information on enthalpy and entropy contributions to binding, which, together with docking studies, were used for structure–activity relationship analysis. Enzymatic assays revealed that N-leucinyl benzenesulfonamides display remarkable selectivity for E. coli leucyl-tRNA synthetase compared to S. aureus and human orthologues. The simplest analogue of the series, N-leucinyl benzenesulfonamide (R = H), showed the highest affinity against E. coli leucyl-tRNA synthetase and also exhibited antibacterial activity against Gram-negative pathogens (the best MIC = 8 μg/mL, E. coli ATCC 25922), which renders it as a promising template for antibacterial drug discovery.
中文翻译：
N-亮氨酰苯甲酰胺作为结构简化的亮氨酰tRNA合成酶抑制剂
已发现N-亮氨酰苯磺酰胺是一类新型的大肠杆菌亮氨酰-tRNA合成酶的有效抑制剂。抑制剂与酶的结合通过使用等温滴定热法来测量。这提供了关于焓和熵对结合的贡献的信息，这些信息与对接研究一起用于结构-活性关系分析。酶法测定显示，与金黄色葡萄球菌和人类直系同源物相比，N-亮氨酰苯磺酰胺对大肠杆菌亮氨酰-tRNA合成酶显示出显着的选择性。该系列中最简单的类似物N-亮氨酰苯磺酰胺（R = H）对大肠杆菌表现出最高的亲和力亮氨酰tRNA合成酶，并且还显示出对革兰氏阴性病原体的抗菌活性（最佳MIC = 8μg/ mL，大肠杆菌ATCC 25922），这使其成为抗菌药物发现的有希望的模板。
更新日期：2018-01-23
中文翻译：
N-亮氨酰苯甲酰胺作为结构简化的亮氨酰tRNA合成酶抑制剂
已发现N-亮氨酰苯磺酰胺是一类新型的大肠杆菌亮氨酰-tRNA合成酶的有效抑制剂。抑制剂与酶的结合通过使用等温滴定热法来测量。这提供了关于焓和熵对结合的贡献的信息，这些信息与对接研究一起用于结构-活性关系分析。酶法测定显示，与金黄色葡萄球菌和人类直系同源物相比，N-亮氨酰苯磺酰胺对大肠杆菌亮氨酰-tRNA合成酶显示出显着的选择性。该系列中最简单的类似物N-亮氨酰苯磺酰胺（R = H）对大肠杆菌表现出最高的亲和力亮氨酰tRNA合成酶，并且还显示出对革兰氏阴性病原体的抗菌活性（最佳MIC = 8μg/ mL，大肠杆菌ATCC 25922），这使其成为抗菌药物发现的有希望的模板。
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