SORA

Advancing, promoting and sharing knowledge of health through excellence in teaching, clinical practice and research into the prevention and treatment of illness

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

Charlton, MH; Aleksis, R; Saint-Leger, A; Gupta, A; Loza, E; Ribas de Pouplana, L; Kaula, I; Gustina, D; Madre, M; Lola, D; et al. Charlton, MH; Aleksis, R; Saint-Leger, A; Gupta, A; Loza, E; Ribas de Pouplana, L; Kaula, I; Gustina, D; Madre, M; Lola, D; Jaudzems, K; Edmund, G; Randall, CP; Kime, L; O'Neill, AJ; Goessens, W; Jirgensons, A; Finn, PW (2018) N-Leucinyl Benzenesulfonamides as Structurally Simplified Leucyl-tRNA Synthetase Inhibitors. ACS Med Chem Lett, 9 (2). pp. 84-88. ISSN 1948-5875 https://doi.org/10.1021/acsmedchemlett.7b00374
SGUL Authors: Gupta, Arya

[img]
Preview
PDF Accepted Version
Available under License ["licenses_description_publisher" not defined].

Download (195kB) | Preview

Abstract

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.

Item Type: Article
Additional Information: This document is the Accepted Manuscript version of a Published Work that appeared in final form in ACS Medicinal Chemistry Letters, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://pubs.acs.org/doi/pdf/10.1021/acsmedchemlett.7b00374.
Keywords: Leucyl-tRNA synthetase, inhibitors, antibacterial, sulfonamides, isothermal titration calorimetry, 0304 Medicinal and Biomolecular Chemistry, 1115 Pharmacology and Pharmaceutical Sciences, 0305 Organic Chemistry
SGUL Research Institute / Research Centre: Academic Structure > Infection and Immunity Research Institute (INII)
Journal or Publication Title: ACS Med Chem Lett
ISSN: 1948-5875
Language: eng
Dates:
DateEvent
8 February 2018Published
18 January 2018Accepted
Publisher License: Unknown
Projects:
Project IDFunderFunder ID
601725Seventh Framework Programmehttp://dx.doi.org/10.13039/501100004963
PubMed ID: 29456792
Web of Science ID: WOS:000424954600005
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/109807
Publisher's version: https://doi.org/10.1021/acsmedchemlett.7b00374

Actions (login required)

Edit Item Edit Item