Improvement of Aglycone π-Stacking Yields Nanomolar to Sub-nanomolar FimH Antagonists

Antimicrobial resistance has become a serious concern for the treatment of urinary tract infections. In this context, an anti-adhesive approach targeting FimH, a bacterial lectin enabling the attachment of E. coli to host cells, has attracted considerable interest. FimH can adopt a low/medium-affinity state in the absence and a high-affinity state in the presence of shear forces. Until recently, mostly the high-affinity state has been investigated, despite the fact that a therapeutic antagonist should bind predominantly to the low-affinity state. In this communication, we demonstrate that fluorination of biphenyl α-d -mannosides leads to compounds with perfect π–π stacking interactions with the tyrosine gate of FimH, yielding low nanomolar to sub-nanomolar K_D values for the low- and high-affinity states, respectively. The face-to-face alignment of the perfluorinated biphenyl group of FimH ligands and Tyr48 was confirmed by crystal structures as well as ¹H,¹⁵N-HSQC NMR analysis. Finally, fluorination improves pharmacokinetic parameters predictive for oral availability.     

Oxadiazole Derivatives as Dual Orexin Receptor Antagonists: Synthesis,Structure–Activity Relationships,and Sleep-Promoting Properties in Rats

The orexin system plays an important role in the regulation of wakefulness. Suvorexant, a dual orexin receptor antagonist (DORA) is approved for the treatment of primary insomnia. Herein, we outline our optimization efforts toward a novel DORA. We started our investigation with rac-[3-(5-chloro-benzooxazol-2-ylamino)piperidin-1-yl]-(5-methyl-2-[1,2,3]triazol-2-ylphenyl)methanone ( 3 ), a structural hybrid of suvorexant and a piperidine-containing DORA. During the optimization, we resolved liabilities such as chemical instability, CYP3A4 inhibition, and low brain penetration potential. Furthermore, structural modification of the piperidine scaffold was essential to improve potency at the orexin 2 receptor. This work led to the identification of (5-methoxy-4-methyl-2-[1,2,3]triazol-2-ylphenyl)-{(S)-2-[5-(2-trifluoromethoxyphenyl)-[1,2,4]oxadiazol-3-yl]pyrrolidin-1-yl}methanone ( 51 ), a potent, brain-penetrating DORA with in vivo efficacy similar to that of suvorexant in rats.     

Development of Biarylalkyl Carboxylic Acid Amides with Improved Anti-schistosomal Activity

The parasitic disease schistosomiasis is the cause of more than 200 000 human deaths per year. Although the disease is treatable, there is one major shortcoming: praziquantel has been the only drug used to combat these parasites since 1977. The risk of the emergence of resistant schistosomes is known to be increasing, as a reduced sensitivity of these parasites toward praziquantel has been observed. We developed a new class of substances, which are derived from inhibitors of human aldose reductase, and which showed promising activity against Schistosoma mansoni couples in vitro. Further optimisation of the compounds led to an increase in anti-schistosomal activity with observed phenotypes such as reduced egg production, vitality, and motility as well as tegumental damage and gut dilatation. Here, we performed structure–activity relationship studies on the carboxylic acid moiety of biarylalkyl carboxylic acids. Out of 82 carboxylic acid amides, we identified 10 compounds that are active against S. mansoni at 25 μm . The best five compounds showed an anti-schistosomal activity up to 10 μm and induced severe phenotypes. Cytotoxicity tests in human cell lines showed that two derivatives had no cytotoxicity at 50 or 100 μm . These compounds are promising candidates for further optimisation toward the new anti-schistosomal agents.     

Fouling Detection in an Optically Accessible Microstructured Heat Exchanger

The application of highly effective microstructured devices in continuous production and industrial environments is frequently prone to fouling. A new method is presented to characterize fouling in these microstructures. Thermal fouling of aqueous solutions containing whey protein were used as a test system. Different fouling effects could be observed and distinguished. Integral fouling indicators, such as thermal fouling resistance and pressure drop, as conventional criteria for the occurrence of fouling were compared with direct local optical observation. Low thermal fouling resistances could be detected.     

n-Type Doping of Vapor–Liquid–Solid Grown GaAs Nanowires

In this letter, n-type doping of GaAs nanowires grown by metal–organic vapor phase epitaxy in the vapor–liquid–solid growth mode on (111)B GaAs substrates is reported. A low growth temperature of 400°C is adjusted in order to exclude shell growth. The impact of doping precursors on the morphology of GaAs nanowires was investigated. Tetraethyl tin as doping precursor enables heavily n-type doped GaAs nanowires in a relatively small process window while no doping effect could be found for ditertiarybutylsilane. Electrical measurements carried out on single nanowires reveal an axially non-uniform doping profile. Within a number of wires from the same run, the donor concentrations N _D of GaAs nanowires are found to vary from 7 × 10¹⁷ cm^-3 to 2 × 10¹⁸ cm^-3. The n-type conductivity is proven by the transfer characteristics of fabricated nanowire metal–insulator-semiconductor field-effect transistor devices.     

Self-assembled microstructured polymeric and ceramic surfaces

Self-assembled microstructures were manufactured by dip coating of substrates with unfilled and filler-loaded preceramic polymer mixtures in the presence of a solvent and a non-solvent. The nature of the polymers was characterized by their solubility parameters. Variation of the polymer/polymer ratio and the volume fraction of the solvent and/or non-solvent led to different surface structures. Studies of the structure formation mechanism indicate that demixing processes of the polymers are responsible for self-assembly in filler-free mixtures. In filler-loaded mixtures the structure formation process, however, is more complex. The micro-structured polymeric coatings obtained from filler loaded systems were converted into polymer derived ceramic coatings under shape retention. High specific surface areas were measured after thermal conversion.     

Kinetics of nucleation and crystallization in poly(?-caprolactone) (PCL)

The recently developed differential fast scanning calorimetry (DFSC) is used for a new look at the crystal growth of poly(?-caprolactone) (PCL) from 185 K, below the glass transition temperature, to 330 K, close to the equilibrium melting temperature. The DFSC allows temperature control of the sample and determination of its heat capacity using heating rates from 50 to 50,000 K/s. The crystal nucleation and crystallization halftimes were determined simultaneously. The obtained halftimes cover a range from 3 × 10⁻² s (nucleation at 215 K) to 3 × 10⁹ s (crystallization at 185 K). After attempting to analyze the experiments with the classical nucleation and growth model, developed for systems consisting of small molecules, a new methodology is described which addresses the specific problems of crystallization of flexible linear macromolecules. The key problems which are attempted to be resolved concern the differences between the structures of the various entities identified and their specific role in the mechanism of growth. The structures range from configurations having practically unmeasurable latent heats of ordering (nuclei) to being clearly-recognizable, ordered species with rather sharp disordering endotherms in the temperature range from the glass transition to equilibrium melting for increasingly perfect and larger crystals. The mechanisms and kinetics of growth involve also a detailed understanding of the interaction with the surrounding rigid-amorphous fraction (RAF) in dependence of crystal size and perfection.     

Modeling and in-depth analysis of the start-up of dividing-wall columns

Saving potentials of up to 30% in capital and operating costs are the driving forces behind the increase in the application of dividing-wall columns in industry. However, a lack of knowledge still exists when dealing with the start-up of dividing-wall columns, which is inherently a strongly nonlinear process. Here, for the first time the start-up of dividing-wall columns is explored, where the starting point is an empty column at ambient conditions. A model is presented which is capable of predicting the dynamic discrete-continuous changes which are characteristic of dividing-wall columns. The proposed process model takes into account the heat transfer across the dividing wall as well as the vapor distribution below the dividing wall. The degree of accuracy of the model is clearly determined by comparing different simplifications, e.g. a constant vapor distribution ratio equal to the steady-state value. The detailed studies were carried out with strict product specifications so that the influence of process parameters could be quantified. The rigorous process model and the obtained simulation results presented in this study provide a promising basis for developing and applying optimal start-up policies for dividing-wall columns.     

The use of microwave irradiation for the easy synthesis of graphene-supported transition metal nanoparticles in ionic liquids

Stable ruthenium or rhodium metal nanoparticles were supported on chemically derived graphene (CDG) surfaces with small and uniform particle sizes (Ru 2.2 ± 0.4 nm and Rh 2.8 ± 0.5 nm) by decomposition of their metal carbonyl precursors by rapid microwave irradiation in a suspension of CDG in the ionic liquid 1-butyl-3-methylimidazolium tetrafluoroborate. The graphene-supported hybrid nanoparticles were shown to be active and could be re-used at least 10 times as catalysts for the hydrogenation of cyclohexene and benzene under organic-solvent-free conditions with constant activities up to 1570 mol cyclohexane × (mol metal)⁻¹ × h⁻¹ at 4 bar and 75 °C.