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

Direkter Nachweis der renalen Hyperämie nach intravenöser Injektion von Fursemid beim Hund

The effect of intravenous furosemide (1 mg/kg) body weight on the clearance of sodium-para-aminohippurate ( C PAH ) and on renal blood flow (electromagnetic flowmeter) was investigated under Nembutal anesthesia in 6 mongrel dogs. Renal blood flow, after a slight decrease, 20–30 sec after the Furosemide injection, increased rapidly and attained a mean value of +30.0% ( p <0.001) within the first 10 min. During the second 10 min, the increase averaged +23.1% ( p <0.0025) and dropped to +10.6% ( p <0.05) in the third 10 min period. The C PAH showed a similar pattern with mean increases of 24.8% ( p <0.05), 13.0% ( p <0.05) and +6.9% respectively. In 2 dogs, electromagnetic flowmeters were implanted on the renal artery and the same studies peformed without anesthesia. Again renal blood flow and C PAH increased in a similar way to that seen in the previous study, although the increase was slightly more pronounced. We conclude that the observed increase of C PAH in dogs after furosemide reflects a real increase of renal plasma flow and is not merely due to a washout effect. Bei 6 Bastard-Hunden wurde unter Nembutal-Narkose die Wirkung von Fursemid (1,0 mg/kg) Körpergewicht, i.v. injiziert auf die Natrium-Paraaminohippurat-Clearance ( C PAH ) und auf die renale Durchblutung, gemessen mit einem elektromagnetischen Durchflußmesser, untersucht. Die Nierendurchblutung nahm, nach einer wenige Sekunden dauernden leichten Abnahme, regelmäßig zu. Die größte Zunahme, im Mittel +30% ( p <0,001) trat innerhalb der ersten 10 min nach Fursemid auf. In den zweiten 10 min sank die mittlere Zunahme auf +23,1% ( p <0,0025), in den folgenden 10 min auf +10,6% ( p <0,05) ab. Die entsprechenden Werte für die C PAH lauten +24,8% ( p <0,05), +13,0% ( p <0,05) und +6,9% ( p <0,05). Um die Wirkung der Barbiturat-Narkose auszuschalten, wurden bei 2 Hunden mit implantierten elektromagnetischen Druckmessern dieselben Meßgrößen nach Fursemid in derselben Dosierung untersucht. Die Zunahme der Nierendurchblutung und der C PAH tritt auch unter diesen Bedingungen, sogar noch etwas ausgesprochener, auf. Wir schließen aus unseren Befunden daß die nach Fursemid beim Hund auftretende Zunahme der C PAH einer Zunahme der renalen Plasmadurchströmung, resp. der Nierendurchblutung entspricht und nicht auf einem „Auswasch“-Effekt beruht.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46305/1/210_2004_Article_BF00537179.pd

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