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