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

Advances in modeling transport phenomena in material-extrusion additivemanufacturing: Coupling momentum, heat, and mass transfer

Material-extrusion (MatEx) additive manufacturing involves layer-by-layer assembly ofextruded material onto a printer bed and has found applications in rapid prototyping.Both material and machining limitations lead to poor mechanical properties of printedparts. Such problems may be addressed via an improved understanding of thecomplex transport processes and multiphysics associated with the MatEx process.Thereby, this review paper describes the current (last 5 years) state of the art modelingapproaches based on momentum, heat and mass transfer that are employed in aneffort to achieve this understanding. We describe how specific details regardingpolymer chain orientation, viscoelastic behavior and crystallization are often neglectedand demonstrate that there is a key need to couple the transport phenomena. Such acombined modeling approach can expand MatEx applicability to broader applicationspace, thus we present prospective avenues to provide more comprehensive modelingand therefore new insights into enhancing MatEx performanc

Effect of electron-withdrawing substituents on the epoxide ring: an experimental and theoretical electron density analysis of a series of epoxide derivatives

A series of acceptor-substituted epoxide derivatives is scrutinized by means of experimental and theoretical electron-density investigations. Due to the possibility of nucleophilic ring-opening, the epoxide ring is not only a very useful functional group in organic synthesis, but acceptor-substituted epoxides are valuable building blocks for the design of protease inhibitors. Therefore, the electron-density analysis in this work focuses on two main aspects that can contribute to rational drug design: (i) the quantification of the electron-withdrawing substituent effects on the epoxide ring and (ii) the intermolecular interactions involving the epoxide ring in combination with different substituents. It can be shown that the electron-withdrawing properties of the substituents cause an elongation of the C-C bonds in the epoxide rings and the loss of electron density can be measured by an analysis of critical points, atomic charges, and the source function. The different strengths of the substituents are reflected in these properties. Covalent and electrostatic contributions to the intermolecular interactions and thus the lattice energies are depicted on different molecular surfaces