Publications

Abstract The multiobjective optimization technique based on the desirability estimation of several interrelated responses (MOOP-DESIRE) has been recently applied to quantitative structure-activity relationship (QSAR) studies. However, the advantage of applying this new methodology to the study of selectivity and affinity to competitive targets has been little explored. We used the MOOP-DESIRE methodology and a variation of this, to study the arylpiperazine derivates that could interact with 5-HT1A and 5-HT2A. serotonin receptor subtypes with the objective of designing more selective molecules for the 5-HT1A receptor. We did show that the model results are in agreement with the available pharmacophore descriptions, guaranteeing an appropriate structural correlation and proving the methodology, as a useful tool for the important problem of selective drug design.

Abstract Isothermal titration calorimetry (ITC) measurements were performed using solutions of whey protein isolate (WPI) and chitosan with different deacetylation degrees (DD), in acetate buffer solutions, pH 3-6. Turbidity measurements were performed in parallel in order to follow the changes in aggregation. so as to get deeper insight on the interaction mechanism. The viscosity-average molar mass of chitosan was obtained from intrinsic viscosity measurements, and the interaction enthalpies were derived at the studied pH values. Further, the denaturation process of alpha-lactalbumin and beta-lactoglobulin within WPI was characterized by differential scanning calorimetry (DSC). At pH 3, where both chitosan and the proteins are positively charged, a weak carbohydrate-protein interaction is observed. When the pH is raised to 6, where the protein charge is expected to be negative, a much stronger interaction takes place. The results are discussed with special emphasis on the effect of pH on the interactions observed in this complex system.

Abstract More than 100 transthyretin (TTR) variants are associated with hereditary amyloidosis. Approaches for TTR amyloidosis that interfere with any step of the cascade of events leading to fibril formation have therapeutic potential. In this study we tested (-)-epigallocatechin-3-gallate (EGCG), the most abundant catechin of green tea, as an inhibitor of TTR amyloid formation. We demonstrate that EGCG binds to TTR "in vitro" and "ex vivo" and that EGCG inhibits TTR aggregation "in vitro" and in a cell culture system. These findings together with the low toxicity of the compound raise the possibility of using EGCG in a therapeutic approach for familial amyloidotic polyneuropathy, the most frequent form of hereditary TTR amyloidosis. Structured summary: MINT-7294529: TTR (uniprotkb:P02766) and TTR (uniprotkb:P02766) bind (MI:0407) by comigration in non-denaturing gel electrophoresis (MI:0404)

Abstract The crystal structure of 2-thoiphenecarboxamide is described. The compound crystallizes in the orthorhombic Pna2(1) space group with unit cell parameters a = 10.044 (3) angstrom, b = 14.203 (4) angstrom and c = 15.941 (3) angstrom; V = 2,274.1 (10) angstrom(3). The asymmetric unit contains four independent molecules which are linked by N-H center dot center dot center dot O hydrogen bonds. The asymmetric unit at (x, y, z) is connected with another one, produced by the a-glide plane at 0.75 along the b-axis, that lies at (x + 0.5, -y + 1.5, z) by two N-H center dot center dot center dot O hydrogen bonds and by a C-H center dot center dot center dot O weak hydrogen bond to form a one-dimensional tube. Adjacent tubes are linked by C-H center dot center dot center dot pi interactions to form a three-dimensional framework.

Abstract Ion specific effects on the mutual solubilities between hydrophobic ionic liquids (ELs) and water are complex and not fully understood. The aim of this work is to obtain further evidence about the molecular mechanism behind this phenomenon by evaluating the effect of a large series of inorganic and organic salts on the mutual solubilities of water and the ionic liquid 1-butyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide, [C(4)mim][Tf(2)N]. The magnitudes of the salting-in and salting-out effects were assessed by changing either the cation or the anion, in a series of salts, as well as the salt concentration. It was observed that the influence of the ions on the solubility followed the Hofmeister series. Both salting-in and salting-out effects were observed and they showed to be dependent on both the nature of the salt and its concentration, while the pH had only a marginal effect on the studied solubilities. On the basis of the solubility changes of the ionic liquid in water in the presence of salts and on NMR spectroscopic data, it will be shown that salting-out inducing ions (high charge density) and salting-in inducing ions (low charge density) act through different mechanisms. While the former act mainly through an entropic effect resulting from the formation of water-ion hydration complexes which cause the dehydration of the solute and the increase of the surface tension of the cavity, the salting-in results from a direct ion binding of the low charge density ions to the hydrophobic moieties of the solute.

Abstract Self-assembled monolayers (SAMs), prepared by the immersion method, from ethanolic solutions containing alpha,omega-alkanedithiol, n-alkanethiol or mixed thiol/dithiol solutions, with 6, 9 and 10 carbon atoms in the alkyl chain, have been investigated. The amount of adsorbate and the SAM stability in alkaline medium is evaluated by reductive desorption of the prepared monolayers by cyclic voltammetry. An upright orientation of the dithiol self-assembled molecules and disulfide bonding at the SAM/solution interface are suggested by the higher reductive desorption charge of the dithiol monolayers (relative to thiol SAMs) for n = 6 and 9. The results show that an improvement on the stability of these dithiol SAMs is obtained by the presence of monothiols, resulting in mixed monolayers. Mixed SAMs prepared from longer alkane chain thiols, n = 10, allow to overcome the increased possibility of loop formation and therefore lower surface coverage is obtained for the 1,10-decanedithiol monolayers. Morphological characterisation of the modified electrodes is performed by scanning tunnelling microscopy (STM) ex situ, in air. Typical one atom deep thiol induced depressions are observed in the STM images of the dithiol and mixed SAMs.

Abstract In the title compound, C(16)H(16)N(4)O(4), the dihedral angle between the aromatic rings is 79.04 (8)degrees and an intramolecular N-H center dot center dot center dot O hydrogen bond occurs. In the crystal, weak C-H center dot center dot O and C-H center dot center dot center dot pi interactions link the molecules, forming sheets.

Abstract In the title molecule, C(17)H(12)O(2), the dihedral angle between the mean plane of the benzene ring and that of the naphthalene ring system is 49.09 (6)degrees. In the crystal structure, molecules are linked to form centrosymmetric dimers via intermolecular O-H center dot center dot center dot O hydrogen bonds. The hydroxy H atom is disordered over two sites with refined occupancies of 0.62 (3) and 0.38 (3).

Abstract The innate immunity factor lactoferrin harbours two antimicrobial moieties, lactoferricin and lactoferrampin, situated in close proximity in the NI domain of the molecule. Most likely they cooperate in many of the beneficial activities of lactoferrin. To investigate whether chimerization of both peptides forms a functional unit we designed a chimerical structure containing lactoferricin amino acids 17-30 and lactoferrampin amino acids 265-284. The bactericidal activity of this LFchimera was found to be drastically stronger than that of the constituent peptides, as was demonstrated by the need for lower dose, shorter incubation time and less ionic strength dependency. Likewise, strongly enhanced interaction with negatively charged model membranes was found for the LFchimera relative to the constituent peptides. Thus, chimerization of the two antimicrobial peptides resembling their structural orientation in the native molecule strikingly improves their biological activity.

Abstract A thermochemical and thermophysical study has been carried out for crystalline barbital [5,5'-diethyl-barbituric acid]. The thermochemical study was made by static bomb combustion calorimetry, from which the standard (p degrees = 0.1 MPa) molar enthalpy of formation of the crystalline barbital, at T = 298.15 K, was derived as -(753.0 +/- 1.8) kJ . mol(-1). The thermophysical study was made by differential scanning calorimetry over the temperature interval (265 to 470) K. A solid-solid phase transition was found at T = 413.3 K. The vapour pressures of the crystalline barbital were measured at several temperatures between T = (355 and 377) K, by the Knudsen mass-loss effusion technique, from which the standard molar enthalpy of sublimation, at T = 298.15 K was derived as (117.3 +/- 0.6) kJ . mol(-1). The combination of the experimental results yielded the standard molar enthalpy of formation of barbital in the gaseous phase, at T = 298.15 K, as -(635.8 +/- 1.9) kJ . mol(-1). This value is compared and discussed with our theoretical calculations by several methods (Gaussian-n theories G2 and G3, complete basis set CBS-QB3, density functional B3P86 and B3LYP) by means of atomization and isodesmic reaction schemes.