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ACS Med Chem Lett. 2018 Jan 18;9(2):84-88. doi: 10.1021/acsmedchemlett.7b00374. eCollection 2018 Feb 8.

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

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Oxford Drug Design Ltd., Oxford Centre for Innovation, New Road, Oxford, OX1 1BY. U.K.
Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga LV-1006, Latvia.
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac, 10, 08028 Barcelona, Catalonia, Spain.
ICREA, Pg. Lluís Company 23, 08010 Barcelona, Catalonia, Spain.
Antimicrobial Research Centre and School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, U.K.
Erasmus University Medical Center Rotterdam, Department of Medical Microbiology and Infectious Diseases, Wytemaweg 80, 3015 CN, Rotterdam, The Netherlands.
Department of Applied Computing, University of Buckingham, Hunter Street, Buckingham, MK18 1EG, U.K.


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.

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