N-Leucinyl Benzenesulfonamides as Structurally Simplified Leucyl-tRNA Synthetase Inhibitors

被引：15

作者：

Charlton, Michael H. ^{[1
]}

Aleksis, Rihards ^{[2
]}

Saint-Leger, Adelaide ^{[3
,4
]}

Gupta, Arya ^{[5
,6
,9
]}

Loza, Einars ^{[2
]}

Ribas de Pouplana, Lluis ^{[3
]}

Kaula, Ilze ^{[2
]}

Gustina, Daina ^{[2
]}

Madre, Marina ^{[2
]}

Lola, Daina ^{[2
]}

Jaudzems, Kristaps ^{[2
]}

Edmund, Grace ^{[1
]}

Randall, Christopher P. ^{[5
,6
]}

Kime, Louise ^{[5
,6
]}

O'Neill, Alex J. ^{[5
,6
]}

Goessens, Wil ^{[7
]}

Jirgensons, Aigars ^{[2
]}

Finn, Paul W. ^{[1
,8
]}

机构：

[1] Oxford Drug Design Ltd, Oxford Ctr Innovat, New Rd, Oxford OX1 1BY, England

[2] Latvian Inst Organ Synth, Aizkraukles 21, LV-1006 Riga, Latvia

[3] Barcelona Inst Sci & Technol, Inst Res Biomed IRB Barcelona, Baldiri Reixac 10, Barcelona 08028, Catalonia, Spain

[4] ICREA, Pg Lluis Co 23, Barcelona 08010, Catalonia, Spain

[5] Univ Leeds, Fac Biol Sci, Antimicrobial Res Ctr, Leeds LS2 9JT, W Yorkshire, England

[6] Univ Leeds, Fac Biol Sci, Sch Mol & Cellular Biol, Leeds LS2 9JT, W Yorkshire, England

[7] Erasmus Univ, Med Ctr Rotterdam, Dept Med Microbiol & Infect Dis, Wytemaweg 80, NL-3015 CN Rotterdam, Netherlands

[8] Univ Buckingham, Dept Appl Comp, Hunter St, Buckingham MK18 1EG, England

[9] Univ London, Inst Infect & Immun St Georges, London SW17 0RE, England

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2018年 / 9卷 / 02期

关键词：

Leucyl-tRNA synthetase; inhibitors; antibacterial; sulfonamides; isothermal titration calorimetry; STAPHYLOCOCCUS-AUREUS; ANTIMICROBIAL AGENTS; DISCOVERY; ANTIBACTERIALS; GSK2251052; BACTERIA;

D O I：

10.1021/acsmedchemlett.7b00374

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 mu g/mL, E. coli ATCC 25922), which renders it as a promising template for antibacterial drug discovery.

引用

页码：84 / 88

页数：5

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