Potent covalent inhibitors of bacterial urease identified by activity-reactivity profiling |
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Authors: | Katarzyna Macegoniuk Rafa? Kowalczyk Anna Rudzińska Mateusz Psurski Joanna Wietrzyk ?ukasz Berlicki |
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Institution: | 1. Department of Bioorganic Chemistry, Faculty of Chemistry, Wroc?aw University of Technology, Wybrze?e Wyspiańskiego 27, 50-370 Wroc?aw, Poland;2. Department of Organic Chemistry, Faculty of Chemistry, Wroc?aw University of Technology, Wybrze?e Wyspiańskiego 27, 50-370 Wroc?aw, Poland;3. Laboratory of Experimental Anticancer Therapy, Department of Experimental Oncology, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Weigla 12, 53-114 Wroc?aw, Poland |
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Abstract: | Covalent enzyme inhibitors constitute a highly important group of biologically active compounds, with numerous drugs available on the market. Although the discovery of inhibitors of urease, a urea hydrolyzing enzyme crucial for the survival of some human pathogens, is a field of medicinal chemistry that has grown in recent years, covalent urease inhibitors have been rarely investigated until now. Forty Michael acceptor-type compounds were screened for their inhibitory activities against bacterial urease, and several structures exhibited high potency in the nanomolar range. The correlation between chemical reactivity towards thiols and inhibitory potency indicated the most valuable compound — acetylenedicarboxylic acid, with nM and . Molecular modelling studies revealed that acetylenedicarboxylic acid is the first example of highly effective mode of binding based on simultaneous bonding to a cysteine residue and interaction with nickel ions present in the active site. Activity-reactivity profiling of reversible covalent enzyme inhibitors is a general method for the identification of valuable drug candidates. |
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Keywords: | AHA acetohydroxamic acid GHS glutathione PBMC peripheral blood mononuclear cells PI propidium iodide SRB sulforhodamine B Tol tollyl Michael acceptors Cysteine Glutathione Cytotoxicity Thiols |
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