Synthesis and structure-activity studies of novel anhydrohexitol-based Leucyl-tRNA synthetase inhibitors
| Autor: | Arthur Van Aerschot, L. Pang, Jef Rozenski, Paul Cos, Dries De Ruysscher, Stijn M.G. Lenders, Stephen D. Weeks, Davie Cappoen, Sergei V. Strelkov |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Models
Molecular Staphylococcus aureus Antifungal Agents Triazole Microbial Sensitivity Tests Crystallography X-Ray 01 natural sciences 03 medical and health sciences chemistry.chemical_compound Structure-Activity Relationship Sugar Alcohols Drug Discovery Candida albicans Escherichia coli Structure–activity relationship Enzyme Inhibitors 030304 developmental biology Pharmacology chemistry.chemical_classification 0303 health sciences Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Leucyl-tRNA synthetase Pharmacology. Therapy Organic Chemistry General Medicine Mycobacterium tuberculosis Structure-activity relationship Antimicrobial Neisseria gonorrhoeae 0104 chemical sciences Anti-Bacterial Agents Enzyme inhibition Enzyme Biochemistry chemistry Leucine-tRNA Ligase Bi-substrate competitive inhibitors Leucine Antibacterial activity Nucleoside Protein-ligand co-crystal structures |
| Zdroj: | European journal of medicinal chemistry |
| ISSN: | 0223-5234 |
| Popis: | Leucyl-tRNA synthetase (LeuRS) is a clinically validated target for the development of antimicrobials. This enzyme catalyzes the formation of charged tRNALeu molecules, an essential substrate for protein translation. In the first step of catalysis LeuRS activates leucine using ATP, forming a leucyl-adenylate intermediate. Bi-substrate inhibitors that mimic this chemically labile phosphoanhydride-linked nucleoside have proven to be potent inhibitors of different members of the aminoacyl-tRNA synthetase family but, to date, they have demonstrated poor antibacterial activity. We synthesized a small series of 1,5-anhydrohexitol-based analogues coupled to a variety of triazoles and performed detailed structure-activity relationship studies with bacterial LeuRS. In an in vitro assay, Kiapp values in the nanomolar range were demonstrated. Inhibitory activity differences between the compounds revealed that the polarity and size of the triazole substituents affect binding. X-ray crystallographic studies of N. gonorrhoeae LeuRS in complex with all the inhibitors highlighted the crucial interactions defining their relative enzyme inhibitory activities. We further examined their in vitro antimicrobial properties by screening against several bacterial and yeast strains. While only weak antibacterial activity against M. tuberculosis was detected, the extensive structural data which were obtained could make these LeuRS inhibitors a suitable starting point towards further antibiotic development. ispartof: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY vol:211 ispartof: location:France status: published |
| Databáze: | OpenAIRE |
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