Please use this identifier to cite or link to this item:
http://doi.org/10.25358/openscience-8873
Authors: | Barthels, Fabian Meyr, Jessica Hammerschmidt, Stefan J. Marciniak, Tessa Räder, Hans-Joachim Ziebuhr, Wilma Engels, Bernd Schirmeister, Tanja |
Title: | 2-sulfonylpyrimidines as privileged warheads for the development of S. aureus sortase A inhibitors |
Online publication date: | 2-Mar-2023 |
Year of first publication: | 2021 |
Language: | english |
Abstract: | Staphylococcus aureus is one of the most frequent causes of nosocomial and community-acquired infections, with emerging multiresistant isolates causing a significant burden to public health systems. We identified 2-sulfonylpyrimidines as a new class of potent inhibitors against S. aureus sortase A acting by covalent modification of the active site cysteine 184. Series of derivatives were synthesized to derive structure-activity relationship (SAR) with the most potent compounds displaying low micromolar KI values. Studies on the inhibition selectivity of homologous cysteine proteases showed that 2-sulfonylpyrimidines reacted efficiently with protonated cysteine residues as found in sortase A, though surprisingly, no reaction occurred with the more nucleophilic cysteine residue from imidazolinium-thiolate dyads of cathepsin-like proteases. By means of enzymatic and chemical kinetics as well as quantum chemical calculations, it could be rationalized that the SNAr reaction between protonated cysteine residues and 2-sulfonylpyrimidines proceeds in a concerted fashion, and the mechanism involves a ternary transition state with a conjugated base. Molecular docking and enzyme inhibition at variable pH values allowed us to hypothesize that in sortase A this base is represented by the catalytic histidine 120, which could be substantiated by QM model calculation with 4-methylimidazole as histidine analog. |
DDC: | 570 Biowissenschaften 570 Life sciences 610 Medizin 610 Medical sciences |
Institution: | Johannes Gutenberg-Universität Mainz |
Department: | FB 09 Chemie, Pharmazie u. Geowissensch. |
Place: | Mainz |
ROR: | https://ror.org/023b0x485 |
DOI: | http://doi.org/10.25358/openscience-8873 |
Version: | Published version |
Publication type: | Zeitschriftenaufsatz |
License: | CC BY |
Information on rights of use: | https://creativecommons.org/licenses/by/4.0/ |
Journal: | Frontiers in molecular biosciences 8 |
Pages or article number: | 804970 |
Publisher: | Frontiers |
Publisher place: | Lausanne |
Issue date: | 2021 |
ISSN: | 2296-889X |
Publisher DOI: | 10.3389/fmolb.2021.804970 |
Appears in collections: | JGU-Publikationen |
Files in This Item:
File | Description | Size | Format | ||
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![]() | 2sulfonylpyrimidines_as_privi-20230302115838017.pdf | 2.52 MB | Adobe PDF | View/Open |