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2H NMR quadrupole splittings and longitudal relaxation times from the aromatics ring of benzyl alcohol-d5(Co), a commonly used anesthetic, and a series of linear alkyl benzyl-d5 ethers with chain lengths from 1 to 12 carbon atoms were measured. Both experiment and theory suggest that an aliphatic chain of about eight or nine carbon is sufficiently hydrophobic to completely align the guest molecule inside the aggregate.

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Most drugs have to cross cell membranes to reach their final target. A better understanding of the distribution, interactions, and dynamics of biologically active molecules in model bilayers is of fundamental importance in understanding drug functioning and design. 2H NMR quadrupole splittings (ΔνQ) and longitudinal relaxation times (T1) from the aromatic ring of benzyl alcohol-d5 (C0), a commonly used anesthetic, and a series of linear alkyl benzyl-d5 ethers with chain lengths from 1 to 12 carbon atoms (C1−C12), were measured. The molecules were dissolved in a nematic discotic lyotropic liquid crystal solution made of tetradecyltrimethylammonium chloride (TTAC)/decanol (DeOH)/NaCl/H2O. Values of ΔνQ and T1 from 1,1-dideuteriodecanol (15% enriched) and DHO (H2O with 0.2% D2O) were also measured. ΔνQ of DeOH and DHO remained constant throughout the series. The value of ΔνQ of the para position of the ring (Δνp) in C1 is 30% smaller than the Δνp of C0. This is attributed to the existence of an H-bond between the alcohol hydroxyl proton and the solvent, which influences the average orientation of the ring. The relaxation data show that T1o,m is always longer than T1p and both decrease with the increase in alkyl chain length. Molecular dynamics simulations of the experimentally studied systems were performed. The aggregate was represented as a bilayer. The distribution, average orientation, and order parameters of the aromatic ring of the guest molecules in the bilayer were examined. Rotational correlation functions of all the C−D bonds and the OH bond from H2O were evaluated, allowing an estimate of the correlation times and T1. According to these results all spins relax in extreme narrowing conditions, except DeOH. Experimental and calculated T1 values differ at most by a factor of 3. However, the order of magnitude and the observed trends are well reproduced by the calculations. The aromatic ring of C0 possesses a unique average orientation in the bilayer. For the ether series, the orientation is modified and the C2 symmetry axis of the aromatic ring is exchanging between two orientations averaging the quadrupole splittings from the ortho and meta positions. The simulation supports the existence of an H-bond between C0 and the solvent not found in the ethers, which should be responsible for the observed differences. [ABSTRACT FROM AUTHOR]

We present an enhanced method for synthesizing a novel compound, 1-(4-phenylquinolin-2-yl)propan-1-one ( 3 ), through the solvent-free Friedländer quinoline synthesis using poly(phosphoric acid) as an assisting agent. The crystal structure of compound 3 is analyzed using FT-IR, and the chemical shifts of its 1 H- and 13 C NMR spectra are measured and calculated using B3LYP/6-311G(d,p), CAM-B3LYP/6-311G(d,p), and M06-2X/6-311G(d,p) basis sets in the gas phase. Additionally, the optimized geometry of quinoline 3 is compared with experimental X-ray diffraction values. Through density functional theory calculations, we explore various aspects of the compound's properties, including noncovalent interactions, Hirshfeld surface analysis, nonlinear optical properties, thermodynamic properties, molecular electrostatic potential, and frontier molecular orbitals. These investigations reveal chemically active sites within this quinoline derivative that contribute to its chemical reactivity., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

Tau protein is a natively unfolded protein whose primary role is to participate in axonal transport closely associated with microtubules. Neurodegenerative disorders including Alzheimer's disease and Tauopathies involved tau protein that is found hyperphosphorylated in vivo ; then, tau is detached from microtubules to form toxic aggregates or oligomers, which have a deleterious effect on membranes, triggering an inflammatory response. Considering finding tau inhibitors, we isolated two compounds in the ethyl acetate extract from Xanthoria ectaneoides (Nyl.) Zahlbr; ergosterol peroxide ( 1 ) and a new anthraquinone ( 2 ). We established the structure through spectroscopic data and biogenic considerations, and we named it "2-hydroxy-3-((8-hydroxy-3-methoxy-6-methylanthraquinonyl)oxy)propanoic acid". This new anthraquinone was evaluated as a tau inhibitor by ThT fluorescence, dot blot assays and total internal reflection fluorescence microscopy. Our results strongly suggest that this anthraquinone remodels soluble oligomers and diminishes β-sheet content. Moreover, through the fluorescence labeling of cysteine inside of the microtubule-binding domain (4R), we showed that this anthraquinone could reduce the oligomers progression by inhibiting cysteine interactions., Competing Interests: The authors declare no conflict of interest.

The selective binding behavior of a trimethylammonium-derived pillar[5]arene towards different guests in aqueous media and under neutral conditions is reported. Although it is known that this macrocycle has the capability to form complexes with guests, we anticipate that the intrinsic pillar shape of the macrocycle with two positively charged rims should allow a diversity of binding modes. The three guests were selected based on their charge and size. The inclusion binding modes and the affinity of the macrocycle to form host-guest complexes were determined by ITC and NMR techniques. We reveal the ability of a cationic water soluble pillar[5]arene to effectively complex two guest molecules, one in each rim, evidencing the diversity of binding modes. Two different structures for 1 : 1 and three for 1 : 2 complexes are reported showing the pillararene ability for internal/external binding.

Based on a known pharmacophore model for 5-HT₆ receptor antagonists, a series of novel extended derivatives of the N-arylsulfonyindole scaffold were designed and identified as a new class of 5-HT₆ receptor modulators. Eight of the compounds exhibited moderate to high binding affinities and displayed antagonist profile in 5-HT₆ receptor functional assays. Compounds 2-(4-(2-methoxyphenyl)piperazin-1-yl)-1-(1-tosyl-1H-indol-3-yl)ethanol (4b), 1-(1-(4-iodophenylsulfonyl)-1H-indol-3-yl)-2-(4-(2-methoxyphenyl)piperazin-1-yl)ethanol (4g) and 2-(4-(2-methoxyphenyl)piperazin-1-yl)-1-(1-(naphthalen-1-ylsulfonyl)-1H-indol-3-yl)ethanol (4j) showed the best binding affinity (4b pKi = 7.87; 4g pKi = 7.73; 4j pKi = 7.83). Additionally, compound 4j was identified as a highly potent antagonist (IC50 = 32 nM) in calcium mobilisation functional assay.

A kinetic study on dinitrophenylphosphate monoester hydrolysis in the presence of a cationic pillararene, P5A, has been carried out. Formation of the supramolecular complex between phosphate ester and P5A has been studied by NMR showing complexation-induced upfield proton shifts indicative of aromatic ring inclusion in the pillararene cavity. Molecular dynamic calculations allow structure characterization for the 1 : 1 and 1 : 2 complexes. As a result of the supramolecular interaction both the acidity of DNPP and its hydrolysis rate constants are increased. Catalysis results from combination of both electrostatic stabilization reducing the negative electron density on the PO3(=) oxygens and monoester dianion destabilization by the steric effects of close NMe3(+) groups hindering the hydrogen-bonding with water and destabilising the monoester dianion.

Sticholysin II (St II) is a haemolytic toxin isolated from the sea anemone Stichodactyla helianthus. The high haemolytic activity of this toxin is strongly dependent on the red cell status and the macromolecule conformation. In the present communication we evaluate the effect of human serum albumin on St II haemolytic activity and its capacity to form pores in the bilayer of synthetic liposomes. St II retains its pore forming capacity in the presence of large concentrations (up to 500 μM) of human serum albumin. This effect is observed both in its capacity to produce red blood cells haemolysis and to generate functional pores in liposomes. In particular, the capacity of the toxin to lyse red blood cells increases in the presence of human serum albumin (HSA). Regarding the rate of the pore forming process, it is moderately decreased in liposomes and in red blood cells, in spite of an almost total coverage of the interface by albumin. All the data obtained in red cells and model membranes show that St II remains lytically active even in the presence of high HSA concentrations. This stubbornness can explain why the toxin is able to exert its haemolytic activity on membranes immersed in complex plasma matrixes such as those present in living organisms.

The effect of human serum albumin (HSA) addition on the rate of hydrolysis of the synthetic substrate 4-methylumbelliferyl-β-D-N-N'-N″ triacetylchitotrioside ((NAG)(3)-MUF) catalyzed by hen egg white lysozyme has been measured in aqueous solution (citrate buffer 50 mM pH = 5.2 at 37 °C). The presence of HSA leads to a decrease in the rate of the process. The reaction follows a Michaelis-Menten mechanism under all the conditions employed. The catalytic rate constant decreases tenfold when the albumin concentration increases, while the Michaelis constant remains almost constant in the albumin concentration range employed. Ultracentrifugation experiments indicate that the main origin of the observed variation in the kinetic behavior is related to the existence of an HSA-lysozyme interaction. Interestingly, the dependence of the catalytic rate constant with albumin concentration parallels the decrease of the free enzyme concentration. We interpret these results in terms of the presence in the system of two enzyme populations; namely, the HSA associated enzyme which does not react and the free enzyme reacting as in the absence of albumin. Other factors such as association of the substrate to albumin or macromolecular crowding effects due to the presence of albumin are discarded. Theoretical modeling of the structure of the HSA-lysozyme complex shows that the Glu35 and Asp52 residues located in the active site of lysozyme are oriented toward the HSA surface. This conformation will inactivate lysozyme molecules bound to HSA.

Aortic dissection is a life-threatening disease that requires immediate surgical intervention. Marfan syndrome is a hereditary disease with an autosomal dominant transmission, which affects the connective tissue, with skeletal, cardiovascular and ocular involvement. It is one of the most prevalent connective tissue disorders, presenting a risk of aortic dissection of approximately 1% even without dilatation of the aorta. When dissection occurs during pregnancy and requires surgical intervention (type A dissection), maternal mortality is high (2096-30%). We report a 38 year-old woman with Marfan syndrome that had an acute type A aortic dissection and severe aortic regurgitation at 37 weeks of gestation. The patient underwent a cesarean section and delivered a healthy baby. Afterwards, aortic valve repair and ascending aortic replacement was successfully performed under circulatory arrest with deep hypothermia. Additionally mitral valve repair for degenerative disease with posterior, autologous pericardium mitral valve ring was performed.

The static fluorescence quenching of pyrene by bromide, at the interface of mixed TTAC/TTAB discotic nematic lyotropic liquid crystals, allowed an estimation of the equilibrium constant for the exchange of chloride by bromide. The affinity of the interface for bromide is much higher than for chloride (K(Br-/Cl-) = 13.2). For a molecular level understanding of the experimental results of this and the preceding paper, 20 ns molecular dynamics (MD) simulations were calculated for samples with TTAB/TTAC molar percent ratios 100/0 (A), 50/50 (B) and 0/100 (C). The increment in the concentration of chloride induces a wider distribution of ammonium headgroups along the axis normal to the bilayer surface, increasing the width of the interface. The charge density profile of simulation B shows that the concentration of bromide is higher than the concentration of chloride in the vicinity the ammonium headgroups. The short range contribution to the electrostatic energy from the ammonium-ammonium repulsion is 291.7 kJ/mol for TTAC and 195.6 kJ/mol for TTAB, and the short range ammonium-halide interaction is -6166 kJ/mol for TTAC and -6607 kJ/mol for TTAB, from simulations A and C, respectively. These results are in agreement with a more neutralized TTAB interface. Consistently, the electric dipole moments of water are significantly more aligned with the larger electric field of the TTAB interface.

Counterion and composition effects on the size and interface dynamics of discotic nematic lyotropic liquid crystals made of tetradecyltrimethylammonium halide (TTAX)-decanol (DeOH)-water-NaX, with X = Cl(-) and Br(-), were investigated using NMR and fluorescence spectroscopies. The dynamics of the interface was examined by measuring deuterium quadrupole splittings from HDO (0.1% D(2)O in H(2)O) and 1,1-dideuterodecanol (20% 1,1-dideuterodecanol in DeOH) in 27 samples of each liquid crystal. Aggregation numbers, N(D), from 15 samples of each mesophase were obtained using the fluorescence of pyrene quenched by hexadecylpyridinium chloride. N(D) of TTAB and TTAC are about 230+/-30 and 300+/-20, respectively. N(D) of TTAC increases with increasing concentration of all mesophase components, whereas TTAB shows no correlation between size and composition. The dimension of these aggregates prevents the occurrence of undulations, previously observed in lamellar phases. The quadrupole splitting of decanol-d(2) in TTAC is about 5 kHz smaller than in TTAB, and the splitting of HDO is observed only in TTAB. All results are consistent with a more dynamic TTAC interface. The TTAC aggregate should be more dissociated from counterions and the excess ammonium-ammonium electrostatic repulsions contribute to increase the mobility of the interface components.