85 research outputs found
2-Sulfonylpyrimidines as Privileged Warheads for the Development of S. aureus Sortase A Inhibitors
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 K(I) 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 S ( N )Ar 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
First-principles modeling of the polycyclic aromatic hydrocarbons reduction
Density functional theory modelling of the reduction of realistic
nanographene molecules (C42H18, C48H18 and C60H24) by molecular hydrogen
evidences for the presence of limits in the hydrogenation process. These limits
caused the contentions between three-fold symmetry of polycyclic aromatic
hydrocarbon molecules and two-fold symmetry of adsorbed hydrogen pairs.
Increase of the binding energy between nanographenes during reduction is also
discussed as possible cause of the experimentally observed limited
hydrogenation of studied nanographenes.Comment: 18 pages, 7 figures, accepted to J. Phys. Chem.
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