From Oxadiazole to Triazole Analogues: Optimization toward a Dual Orexin Receptor Antagonist with Improved in vivo Efficacy in Dogs

The orexin system is responsible for regulating the sleep-wake cycle. Suvorexant, a dual orexin receptor antagonist (DORA) is approved by the FDA for the treatment of insomnia disorders. Herein, we report the optimization efforts toward a DORA, where our starting point was (5-methoxy-4-methyl-2-[1,2,3]triazol-2-yl-phenyl)-{(S)-2-[5-(2-trifluoromethoxy-phenyl)-[1,2,4]oxadiazol-3-yl]-pyrrolidin-1-yl}methanone ( 6 ), a compound which emerged from our in-house research program. Compound 6 was shown to be a potent, brain-penetrating DORA with in vivo efficacy similar to suvorexant in rats. However, shortcomings from low metabolic stability, high plasma protein binding (PPB), low brain free fraction (f_u brain), and low aqueous solubility, were identified and hence, compound 6 was not an ideal candidate for further development. Our optimization efforts addressing the above-mentioned shortcomings resulted in the identification of (4-chloro-2-[1,2,3]triazol-2-yl-phenyl)-{(S)-2-methyl-2-[5-(2-trifluoromethoxy-phenyl)-4H-[1,2,4]triazol-3-yl]-pyrrolidin-1-yl}l-methanone ( 42 ), a DORA with improved in vivo efficacy compared to 6 .     

Structural Consequences of the 1,2,3-Triazole as an Amide Bioisostere in Analogues of the Cystic Fibrosis Drugs VX-809 and VX-770

Although the 1,2,3-triazole is a commonly used amide bioisostere in medicinal chemistry, the structural implications of this replacement have not been fully studied. Employing X-ray crystallography and computational studies, we report the spatial and electronic consequences of replacing an amide with the triazole in analogues of cystic fibrosis drugs in the VX-770 and VX-809 series. Crystallographic analyses quantify subtle differences in the relative positions and conformational preferences of the R¹ and R² substituents attached to the amide and triazole bioisosteres. Computational studies derived from the X-ray data highlight the improved hydrogen bonding donor and acceptor capabilities of the amide in comparison to the triazole. This analysis of the spatial and electronic differences between the amide and 1,2,3-triazole will inform medicinal chemists as they consider using the triazole as an amide bioisostere.     

Fox Hunting in Wild Apples: Searching for Novel Genes in Malus Sieversii

Malus sieversii is considered the progenitor of modern apple (Malus pumila) cultivars and to represent a valuable source of genetic diversity. Despite the importance of M. sieversii as a source of disease resistance, stress tolerance, and novel fruit traits, little is known about gene function and diversity in M. sieversii. Notably, a publicly annotated genome sequence for this species is not available. In the current study, the FOX (Full-length cDNA OvereXpressing) gene hunting system was used to construct a library of transgenic lines of Arabidopsis in which each transgenic line overexpresses a full-length gene obtained from a cDNA library of the PI619283 accession of M. sieversii. The cDNA library was constructed from mRNA obtained from bark tissues collected in late fall–early winter, a time at which many abiotic stress-adaptative genes are expressed. Over 4000 apple FOX Arabidopsis lines have been established from the pool of transgenic seeds and cDNA inserts corresponding to various Gene Ontology (GO) categories have been identified. A total of 160 inserts appear to be novel, with no or limited homology to M. pumila, Arabidopsis, or poplar. Over 1300 lines have also been screened for freezing resistance. The constructed library of transgenic lines provides a valuable genetic resource for exploring gene function and diversity in Malus sieversii. Notably, no such library of t-DNA lines currently exists for any Malus species.     

Experimental study and modelling of an azo colourant dynamic adsorption onto functional cross-linked chitosan/ceramic particles in a fixed bed column

The use of azo dyes in industrial activities generates a large volume of contaminated wastewater; these pollutants in water bodies affect aquatic biota and human health. A functional biocomposite sorbent material was synthesized using cross-linked chitosan with oxalic acid that forms a coating on alumina ceramic particles (AOCh). The removal of Reactive Red 195, a reactive azo dye, using a fixed-bed adsorption column filled with this material was tested. AOCh was physico-chemically characterized by Fourier transform infrared spectroscopy–total attenuated reflection (FTIR-ATR), scanning electron microscopy–energy dispersion spectrometry X-ray (SEM-EDS), X-ray diffraction (XDR), thermo-gravimetric analysis (TGA), and Z-potential. The dynamic adsorption performance was analyzed from experimental breakthrough curves obtained in fixed-bed columns by modifying different operating conditions (bed depth, volumetric flow rate, and dye inlet concentration). Equilibrium adsorption isotherms were determined under dynamic conditions and compared with batch results. The maximum adsorption capacity of the dynamic equilibrium isotherm obtained from the continuous assays was 331 mg/g; this value was the highest in comparison to other tested materials reported in the literature. Different dynamic adsorption models were applied to fit experimental data, including Thomas, Bohart–Admas, Yoon–Nelson, logistic general model, bed depth surface time (BDST), and modified dose response (Yan) models. A critical analysis of these equations was presented, showing the equivalences and the relationship among the coefficients. The Yan model achieved the highest level of agreement between the experimental and predicted values of the breakthrough curves. The use of this model enables scaling-up the industrial process for dye removal. The present work proposed a novel biosorbent material and contributes to the analysis of industrial dye removal under dynamic conditions.     

Refractive index and lattice parameter prediction for garnets (A3B2C3X12)

The validity of prediction methods for garnet lattice parameters was tested, and a modified model with best fit to a lattice parameter database with over 1000 garnet compositions was developed. The lattice parameter predictions were used in Shannon and Fischer's model to predict garnet refractive indices. The predictions were compared to refractive index measurements reported for 143 garnet compositions. After calibration of electron overlap factors used in the model, the average prediction error was 1.13%. Sources of error in the models are discussed, as well as applications of the predictive methods.     

Corrosion behavior of Monofrax K-3 refractory in borosilicate-based model low activity waste glass melts

Owing to its good chemical and thermal durabilities at high temperatures, Monofrax K-3 refractory is widely used in nuclear waste vitrification as a lining material in melting vessels. However, the corrosion of K-3 refractory during the vitrification of nuclear waste is a serious problem because it affects the melter's safety, performance, and lifetime. Therefore, in the present study, we have focused on unearthing the impact of glass network formers, such as SiO₂, B₂O₃, and Al₂O₃, in a model nuclear waste glass composition on the corrosion of Monofrax K-3 refractory. The corrosion tests have been performed per ASTM C621 at 1150°C for 5 days. The dimensional measurements on corroded K-3 refractory suggest that Al₂O₃ and SiO₂ tend to reduce the refractory corrosion (neck loss), with the effect of Al₂O₃ being significant. A corroded region on the K-3 refractory at the melt–refractory interface is observed. The corrosion occurs via a coupling of the melt infiltration induced by a capillary effect and the dissolution of Al, Mg, and Fe components from K-3 into the melt through chemical reactions. A Cr-rich layer is retained on the glass contact surface of the corroded K-3 refractory.     

Mixed modifier effect in Na2O·K2O·CaO aluminosilicate glasses: Pairwise and ternary interactions

The mixed modifier effect (MME) is one of the most challenging puzzles in the field of oxide glasses, as there exists no universal quantitative theoretical model for accurately describing and predicting the nonlinear deviation of property values. In this paper, pairwise and ternary interactions are examined experimentally to understand the MME in a series of aluminosilicate glasses. By keeping the glass network former concentration constant and adjusting the molar ratios of three network modifiers (Na₂O, K₂O, and CaO), the MMEs in glass transition temperature (T_g), Vickers hardness (H_v), and activation energy (E_a) for aqueous dissolution for each modifier cation are investigated. We examine whether a pairwise interaction model is sufficient, or if ternary interactions also need to be included to predict the MME in these aluminosilicate glass systems. This work reveals that the pairwise model can be used to predict the MME for T_g in complex multiple-modifier glass systems using only two-body interaction factors. However, ternary mixed-modifier interactions are present in other properties such as H_v and E_a.     

Interlaboratory study on lipid oxidation during accelerated storage trials with rapeseed and sunflower oil analyzed by conjugated dienes as primary oxidation products

Accelerated storage tests are frequently used to assess the oxidative stability of foods and related systems due to its reproducibility. Various methods and experimental conditions are used to measure lipid oxidation. Differences between laboratories make it necessary to determine the repeatability and reproducibility of oxidation tests performed under the same conditions. The objective of the present interlaboratory study was to evaluate the outcome of a storage test for two different bulk oils, sunflower oil (SFO) and rapeseed oil (RSO), during a period of 9 weeks at 20°C, 30°C, 40°C, and 60°C. Sixteen laboratories were provided with bottled oils and conducted the storage tests according to a detailed protocol. Lipid oxidation was monitored by the formation of conjugated dienes (CD) and the activation energy (E_a) was determined for comparative purposes and statistically evaluated. An increase in CD formation was observed for both oils when the storage temperature was increased in all laboratories. The E_a,1 ranged from 47.9 to 73.3 kJ mol⁻¹ in RSO and from 27.8 to 62.6 kJ mol⁻¹ in SFO, with average values of 58.2 and 46.8 kJ mol⁻¹, respectively. The reproducibility coefficients were 10.9% and 18.2% for RSO and SFO, respectively. Practical applications: In order to compare results on oxidative stability of foods derived from different studies, the reproducibility of storage tests and methods employed to evaluate the oxidation level should be considered. This study provides fundamental data on the reproducibility of lipid oxidation under accelerated storage conditions and defines important parameters to be considered for the conduction of experiments.     

New ultra high molecular weight acrylic processing aids for rigid PVC foaming

Foaming of rigid polyvinyl chloride (PVC) is studied as a function of high molecular weight acrylic processing aids. The industrial process to evaluate quality of foam is discussed in detail. The role of acrylic processing aids to improve melt strength and hence foaming of PVC is explained. It is demonstrated that increase in molecular weight of acrylic processing aids increases its effectiveness. It is found that ultra-high molecular weight processing aids is 25%–30% more efficient than relatively lower, but still high, molecular weight acrylic processing aids. The higher molecular weight processing aids provided comparable foaming performance at lower loading levels. Foaming reduced the density of PVC compounds to 0.32–0.34 g/cm³. More than 1000% expansion is achieved in the melt extrusion process using a chemical blowing agent. Fusion characteristics are also studied. Fusion times for initial fusion peaks are in the range of 42–44 s while the fusion times of the second fusion peaks are in the range of 74–94 s. The higher molecular weight processing aids maintained fusion characteristics of PVC compounds, warranting no significant changes in commercial process.     

Prediction of the Crevice Corrosion Incubation Period of Passive Metals at Elevated Temperatures: Part I — Mathematical Model

Previous researchers have numerically modelled the crevice corrosion of particular classes of metals and alloys. Applicable to passive metals immersed in an appropriate electrolyte, a new crevice corrosion model simulates the general passive crevice corrosion problem. Rapid approach of chemical equilibrium is assumed. Equilibrium constants and transport properties are adjusted for elevated temperature via the correspondence principle (Criss and Cobble, 1964) and the Nernst‐Einstein equation, respectively. The corrosion rate is adjusted for thermal and acidity effects via an Arrhenius expression and a Freundlich isotherm, respectively. Presented in a sequel publication, the predictions compare favourably with experimental results.