Optimization and modeling of the performance of polydimethylsiloxane for pervaporation of ethanol−water mixture

Response surface methodology was used to optimize the performance of pervaporation of ethanol aqueous solution using polydimethylsiloxane hollow-fiber membrane. The effects of four operating conditions, that is, the feed temperature (30–50°C), the feed flow rate (10–50 L/h), ethanol concentration (5–20 wt%), and the vacuum pressure (10–50 KPa) on the membrane selectivity and the total flux of permeation were investigated with response surface methodology. The results showed that a quadratic model was suggested for both selectivity and total flux showing a high accuracy with R² = 0.9999 and 0.9995, respectively. The developed models indicated a significant effect of the four studied factors on both selectivity and total flux with some significant interactions between these factors. The optimum selectivity was 15.56, achieved for a feed temperature of 30°C, feed flow rate of 10 L/h, ethanol concentration of 15 wt%, and a permeate pressure of 10.74 KPa whereas the optimum total flux was 1833.66 g/m².h was observed for at a feed temperature of 50°C, a feed flow rate of 50 L/h, ethanol concentration of 15 wt%, and a permeate pressure of 49.38 KPa.     

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.     

Double Gamers—Can Modified Natural Regulators of Higher Plants Act as Antagonists against Phytopathogens? The Case of Jasmonic Acid Derivatives

As key players in biotic stress response of plants, jasmonic acid (JA) and its derivatives cover a specific and prominent role in pathogens-mediated signaling and hence are promising candidates for a sustainable management of phytopathogenic fungi. Recently, JA directed antimicrobial effects on plant pathogens has been suggested, supporting the theory of oxylipins as double gamers in plant-pathogen interaction. Based on these premises, six derivatives (dihydrojasmone and cis-jasmone, two thiosemicarbazonic derivatives and their corresponding complexes with copper) have been evaluated against 13 fungal species affecting various economically important herbaceous and woody crops, such as cereals, grapes and horticultural crops: Phaeoacremonium minimum, Neofusicoccum parvum, Phaeomoniella chlamydospora, Fomitiporia mediterranea, Fusarium poae, F. culmorum, F. graminearum, F. oxysporum f. sp. lactucae, F. sporotrichioides, Aspergillus flavus, Rhizoctonia solani, Sclerotinia spp. and Verticillium dahliae. The biological activity of these compounds was assessed in terms of growth inhibition and, for the two mycotoxigenic species A. flavus and F. sporotrichioides, also in terms of toxin containment. As expected, the inhibitory effect of molecules greatly varied amongst both genera and species; cis-jasmone thiosemicarbazone in particular has shown the wider range of effectiveness. However, our results show that thiosemicarbazones derivatives are more effective than the parent ketones in limiting fungal growth and mycotoxins production, supporting possible applications for the control of pathogenic fungi.     

Synthesis and Assessment of Fused β-Carboline Derivatives as Kappa Opioid Receptor Agonists

The synthesis of 5-formyl-6-aryl-6H-indolo[3,2,1-de][1,5] naphthyridine-2-carboxylates by reaction between 1-formyl-9H-β-carbolines and cinnamaldehydes in the presence of pyrrolidine in water with microwave irradiation is described. Pharmacophoric modification of the formyl group offered several new fused β-carboline derivatives, which were investigated for their κ-opioid receptor (KOR) agonistic activity. Two compounds 4 a and 4 c produced appreciable agonist activity on KOR with EC₅₀ values of 46±19 and 134±9 nM, respectively. Moreover, compound-induced KOR signaling studies suggested both compounds to be extremely G-protein-biased agonists. The analgesic effect of 4 a was validated by the increase in tail flick latency in mice in a time-dependent manner, which was completely blocked by the KOR-selective antagonist norBNI. Moreover, unlike U50488, an unbiased full KOR agonist, 4 a did not induce sedation. The docking of 4 a with the human KOR was studied to rationalize the result.     

1-Indanone and 1,3-indandione Derivatives as Ligands for Misfolded α-Synuclein Aggregates

The development of imaging agents for in vivo detection of alpha-synuclein (α-syn) pathologies faces several challenges. A major gap in the field is the lack of diverse molecular scaffolds with high affinity and selectivity to α-syn fibrils for in vitro screening assays. Better in vitro scaffolds can instruct the discovery of better in vivo agents. We report the rational design, synthesis, and in vitro evaluation of a series of novel 1-indanone and 1,3-indandione derivatives from a Structure-Activity Relationship (SAR) study centered on some existing α-syn fibril binding ligands. Our results from fibril saturation binding experiments show that two of the lead candidates compounds 8 and 32 bind α-syn fibrils with binding constants (K_d) of 9.0 and 18.8 nM, respectively, and selectivity of greater than 10× for α-syn fibrils compared with amyloid-β (Aβ) and tau fibrils. Our results demonstrate that the lead ligands avidly label all forms of α-syn on PD brain tissue sections, but only the dense core of senile plaques in AD brain tissue, respectively. These results are corroborated by ligand-antibody colocalization data from Syn211, which shows immunoreactivity toward all forms of α-syn aggregates, and Syn303, which displays preferential reactivity toward mature Lewy pathology. Our results reveal that 1-indanone derivatives have desirable properties for the biological evaluation of α-synucleinopathies.     

Synthesis of Aminoethyl-Substituted Piperidine Derivatives as σ1 Receptor Ligands with Antiproliferative Properties

A series of novel σ₁ receptor ligands with a 4-(2-aminoethyl)piperidine scaffold was prepared and biologically evaluated. The underlying concept of our project was the improvement of the lipophilic ligand efficiency of previously synthesized potent σ₁ ligands. The key steps of the synthesis comprise the conjugate addition of phenylboronic acid at dihydropyridin-4(1H)-ones 7 , homologation of the ketones 8 and introduction of diverse amino moieties and piperidine N-substituents. 1-Methylpiperidines showed particular high σ₁ receptor affinity and selectivity over the σ₂ subtype, whilst piperidines with a proton, a tosyl moiety or an ethyl moiety exhibited considerably lower σ₁ affinity. Molecular dynamics simulations with per-residue binding free energy deconvolution demonstrated that different interactions of the basic piperidine-N-atom and its substituents (or the cyclohexane ring) with the lipophilic binding pocket consisting of Leu105, Thr181, Leu182, Ala185, Leu186, Thr202 and Tyr206 are responsible for the different σ₁ receptor affinities. Recorded logD_7.4 and calculated clogP values of 4a and 18a indicate low lipophilicity and thus high lipophilic ligand efficiency. Piperidine 4a inhibited the growth of human non-small cell lung cancer cells A427 to a similar extent as the σ₁ antagonist haloperidol. 1-Methylpiperidines 20a , 21a and 22a showed stronger antiproliferative effects on androgen negative human prostate cancer cells DU145 than the σ₁ ligands NE100 and S1RA.     

The Role of α1-Adrenoceptor Antagonists in the Treatment of Prostate and Other Cancers

This review evaluates the role of α-adrenoceptor antagonists as a potential treatment of prostate cancer (PCa). Cochrane, Google Scholar and Pubmed were accessed to retrieve sixty-two articles for analysis. In vitro studies demonstrate that doxazosin, prazosin and terazosin (quinazoline α-antagonists) induce apoptosis, decrease cell growth, and proliferation in PC-3, LNCaP and DU-145 cell lines. Similarly, the piperazine based naftopidil induced cell cycle arrest and death in LNCaP-E9 cell lines. In contrast, sulphonamide based tamsulosin did not exhibit these effects. In vivo data was consistent with in vitro findings as the quinazoline based α-antagonists prevented angiogenesis and decreased tumour mass in mice models of PCa. Mechanistically the cytotoxic and antitumor effects of the α-antagonists appear largely independent of α 1-blockade. The proposed targets include: VEGF, EGFR, HER2/Neu, caspase 8/3, topoisomerase 1 and other mitochondrial apoptotic inducing factors. These cytotoxic effects could not be evaluated in human studies as prospective trial data is lacking. However, retrospective studies show a decreased incidence of PCa in males exposed to α-antagonists. As human data evaluating the use of α-antagonists as treatments are lacking; well designed, prospective clinical trials are needed to conclusively demonstrate the anticancer properties of quinazoline based α-antagonists in PCa and other cancers.     

Preparation and ionic conduction of CaZr1−xScxO3−α ceramics

A series of CaZr_1−xSc_xO_3−α (x=0, 0.05, 0.10, 0.15) perovskite oxide ceramics were successfully fabricated at 1400 °C for 10 h and then further sintered at 1650 °C for 10 h via a solid-state reaction sintering process. Conductivities of the ceramics were measured under the atmosphere that contains 1% H₂/Ar and 5.63 kPa H₂O/Ar by the electrochemical impedance spectra technique. It was found that the conductivities of CaZr_1−xSc_xO_3−α (x=0, 0.05, 0.10, 0.15) ceramics increased with the increase of the measuring temperature, and the conductivity achieved its maximum value of 2.03×10⁻⁵–6.5×10⁻³ S cm⁻¹ when the doping amount of Sc (x) was 0.10. Additionally, element doping can increase the conductivities and decrease the conductivity activation energies of CaZr_1−xSc_xO_3−α ceramics. The results of transport number measurement indicated that the CaZr_0.9Sc_0.1O_3−α is almost a pure protonic conductor at 500–750 °C, while it is a mixed protonic-oxygen ionic-electronic conductor at 750–1300 °C.     

Design,Synthesis, and Biological Evaluation of (+)-Camphor- and (−)-Fenchone-Based Derivatives as Potent Orthopoxvirus Inhibitors

In this work, a library of (+)-camphor and (−)-fenchone based N-acylhydrazones, amides, and esters, including para-substituted aromatic/hetaromatic/cyclohexane ring was synthesized, with potent orthopoxvirus inhibitors identified among them. Investigations of the structure-activity relationship revealed the significance of the substituent at the para-position of the aromatic ring. Also, the nature of the linker between a hydrophobic moiety and aromatic ring was clarified. Derivatives with p-Cl, p-Br, p-CF_3, and p-NO₂ substituted aromatic ring and derivatives with cyclohexane ring showed the highest antiviral activity against vaccinia virus, cowpox, and ectromelia virus. The hydrazone and the amide group were more favourable as a linker for antiviral activity than the ester group. Compounds 3 b and 7 e with high antiviral activity were examined using the time-of-addition assay and molecular docking study. The results revealed the tested compounds to inhibit the late processes of the orthopoxvirus replication cycle and the p37 viral protein to be a possible biological target.     

Structural and magnetic properties of Yb1−xSrxMnO3

The structural and magnetic properties of YbMnO₃ and Yb_0.82Sr_0.18MnO₃ multiferroics were studied by neutron powder diffraction (NPD), magnetometry and electron spin resonance (ESR) technics in a wide temperature range. Neutron diffraction measurements showed that the substitution of ytterbium ions with strontium ions in hexagonal h - YbMnO₃ (space group P6₃cm) leads to the destabilization of the crystal structure of the last compound and appearance of the mixture of three phases with different structure: hexagonal phase h - Yb_0.95Sr_0.05MnO₃ (space group P6₃cm), orthorhombic phase o - Yb_0.69Sr_0.31MnO₃ (space group Pbnm), hexagonal phase SrMnO₃ (space group P6₃cm). This fact was proved by the ESR measurements in which a several signals due to the phases of different structure were observed. NPD measurements showed that the magnetic structure of h - Yb_0.95Sr_0.05MnO₃ phase is similar to the magnetic structure of the pure h - YbMnO₃ and demonstrate the presence of the antiferromagnetic ordering in the samples. ESR and magnetization measurements of h - YbMnO₃ sample proved the presence of the antiferromagnetic correlations and also they showed the appearance of the ferromagnetically correlated nanoregions.     

Microstructure and characterization of Ag1−xLixNbO3 ceramics

Silver–lithium niobate, Ag_1−xLi_xNbO₃, is a promising candidate for lead-free piezoelectrics. Ceramic samples for x equal 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.08 and 0.1 were synthesized by solid state reaction. Room temperature X-ray studies indicate that all samples consist mainly of perovskite phase. Only small amounts of secondary phases, namely Ag₂Nb₄O₁₁, Ag and LiNbO₃, appear. For x≈0.06 the orthorhombic–rhombohedral morphotropic phase boundary is observed. Excellent piezoelectric properties, recently reported for x>0.1, may be the result of proximity of morphotropic phase boundary. Scanning electron microscopy and secondary ion mass spectroscopy investigations suggest that the secondary phases occur chiefly at the grain boundaries. Dielectric measurements, carried out in a wide temperature range, revealed that Ag_1−xLi_xNbO₃, for x≤0.05, undergoes the same complex sequence of phase transitions as AgNbO₃. On the other hand, for x>0.06, the temperature dependence of dielectric permittivity exhibits only two maxima, related to transitions from the ferroelectric R phase to the antiferroelectric M phase and followed by the paraelectric O phase. The dielectric results obtained confirm the existence of the morphotropic phase boundary.     

Design of Zn1−xCuxO Nanocomposite Ag-Doped as an Efficient Antimicrobial Agent

Journal of Inorganic and Organometallic Polymers and Materials - This study aims at the preparation of antimicrobial nanoparticles hybrid based on silver (Ag) doped Zn1?xCuxO. Zn1?xCuxO...     

Effect of Ge Mole Fraction on Electrical Parameters of Si1−xGex Source Step-FinFET and its Application as an Inverter

Silicon - This paper proposes device geometry of Fin-Field-Effect-Transistor (FinFET) with a step-fin. The source region of the proposed device consists of Si1−xGexand the effects of Ge-mole...     

The carbon nonstoichiometry and the lattice parameter of (Ti1−xWx)C1−y

Various monolithic (Ti,W)C powders were synthesized from mixtures of carbon and oxides by varying the W content. The carbon content in the (Ti,W)C solid solution decreased with increasing W content when the solid solution was sintered at 1510 °C for 1 h. The lattice parameters of the sintered (Ti,W)C ceramics tend to decrease with carbon content. In this study, the changes in the carbon content as a function of the tungsten content were compared with the results obtained using ThemoCalc^® software. The relationship between the lattice parameter and composition was examined using an analytical approach and ab initio simulations.     

Synthesis and Structure-Activity Relationship of Xenocoumacin 1 and Analogues as Inhibitors of Ribosomal Protein Synthesis

Ribosomal protein synthesis is an important target in antibacterial drug discovery. Numerous natural products have served as starting points for the development of antibiotics. We report here the total synthesis of xenocoumacin 1, a natural product that binds to 16S ribosomal RNA at a highly conserved region, as well as analogues thereof. Preliminary structure–activity relationship studies were aimed at understanding and modulating the selectivity between eukaryotic and prokaryotic ribosomes. Modifications were mainly tolerated in the aromatic region. Whole-cell activity against Gram-negative bacteria is limited by efflux and penetration, as demonstrated in genetically modified strains of E. coli. Analogues with high selectivity for eukaryotic ribosomes were identified, but it was not possible to obtain inhibitors selective for bacterial protein synthesis. Achieving high selectivity (albeit not the desired one) was thus possible despite the high homology between eukaryotic and prokaryotic ribosomes in the binding region.     

X-ray diffraction,dielectric and Raman studies of the Ba1−xNaxTi1−x(Nb1−ySby)xO3 ceramics

Ba_1−xNa_xTi_1−x(Nb_1−ySb_y)_xO₃ (BNTNSO) ceramics with compositions (x=0.05; y=0; 0.10; 0.20 and 0.30) have been prepared by conventional solid-state method and sintered in the temperature range 1350–1400 °C. Phase purity and structure are investigated using X-ray diffraction (XRD) data. The structural study showed that our synthesized compounds are single phase and crystallize in the tetragonal system with P4mm space group at room temperature. Based on a phenomenological model, dielectric and Raman properties of BNTNSO compounds have been explored. Referring to this model, dielectric properties of ceramics have been investigated in broad ranges of temperature (100–500 K) and frequency 1–10³ kHz). The dielectric permittivity evolution as a function of temperature and frequency has exhibited a classical ferroelectric character for 0≤y≤0.20 and a relaxor type behavior for y=0.30. The investigation of Raman spectra as a function of temperatures and compositions, confirmed the dielectric behavior. These results indicate that the y=0.20 composition is of extreme significance as far as its technological and industrial applications are concerned, which refers basically to its interesting physical properties and environmentally friendly characters, especially as its transition temperature is equal to the room temperature. The used samples show that the substitution of Nb by Sb favors and maintains the relaxor characters without changing the transition temperature.