Publications

Abstract The development of new drugs always was time consuming and costly. With the development in experimental methods was possible to scan small-compounds libraries in order to find potentially suitable molecules. Nevertheless, these methods are able to so with a very low rate. Protein kinases are a class of enzymes involved in the great majority of cellular process. Due to its presence in many signal pathways, cell cycle and gene expression control mechanisms, this class is one of the major targets for pharmaceutical industries today. Aiming the reduction of time and costs in drug development computational tools started to be used, and commonly called Computer aided drug design (CADD). These methods can be separated in two different types of approaches, structure based (SBDD) and ligand based (LBDD). In order to use structure based methods, information about the 3D structure of the target is needed, normally obtained through x-ray crystallography or NMR. Ligand based methods are preferred when this information is not available. The focus of the present chapter is the structure based methods used in the computer drug discovery and design process targeting kinases. Starting with the visual and energetic analysis of the binding site, it is obtained enough information for the creation of a Pharmacophore model and the application of Virtual Screening process. The results of the screening can then be analysed through Molecular Docking process followed by Molecular Dynamics in order to better simulate the real binding conditions. The obtained complexes can be analysed using energy calculations, in order to better understand the binding process. Within the described procedures, computational tools originate a great amount of useful information since hit discovery from lead optimization. The data obtained can save time and reduce costs in the process of drug design and discovery in a large scale.

Abstract The raising level of awareness regarding the harmful effects of solar radiation has resulted in an increase in the production and use of sunscreens. These commercial products contain ultraviolet (UV) filters that absorb, reflect or scatter UV radiation (290-320 nm for UVB and 320-400 nm for UVA) therefore preventing sunburn, photo-aging and ultimately skin diseases such as skin cancer. A high screening efficiency can only be guaranteed if a UV filter has a high photo-stability. However, UV filters are known to undergo degradation upon exposure to sunlight and chemical substances used in water disinfection such as chlorine, leading to the formation of undesirable byproducts with properties different from the parent compounds. This chapter presents a comprehensive review on the computational studies performed so far on the structural, electronic, energetic and UV absorption properties of some of the most widely used UV-filters and their degradation products (UVFDP). Ab initio and density functional theory (DFT) methods have been used to obtain the molecular structure, energetics and other molecular properties of UVF-DP. UV-Vis absorption spectra and excited state properties have been calculated using the time dependent density functional theory (TD-DFT). The influence of different solvents in these properties has been studied using solution models. Transformation and degradation mechanisms have been established with the aid of computational methods and results indicate that these can be employed to assess the environmental fate of UV-filters.

Abstract A recent report on a density odd-even alternation effect in a homologous series of ionic liquids (alkyltrioctylphosphonium chlorides, with the linear alkyl group ranging from ethyl to decyl) led to the detection of a similar trend in another ionic liquid family based on a different cation (1-alkyl-3-methylimidazolium). Ab initio calculations and Molecular Dynamics simulations of the corresponding ions confirmed that the charge distribution along the alkyl side chains and the conformations adopted by them are not the direct cause of the odd-even effect. The simulations also showed that all cation side chains tend to adopt transoid conformations that pack head-to-head in the liquid phase. Such types of conformations/packing lead to odd-even alternation effects on properties involving solid phases of different molecular compounds containing linear alkyl chains. The surprising results obtained for the ionic liquid series enabled us to unveil similar trends in the liquid phases of linear alkanes and alkanols via the application of a simple corresponding states principle.

Abstract We have studied thermochemical, thermophysical and structural properties of bisphenols A, E, F, and AP. In particular, the standard enthalpies of sublimation and the standard enthalpies of formation in the gas phase at 298.15 K for all these species were experimentally determined. A computational study, through M05-2X density functional theory, of the various species shed light on structural effects and further confirmed, by means of the isodesmic reaction scheme, the excellent consistency of the experimental results. Our results reflect also the fact that energetic substituent effects are transferable from diphenylalkanes to bisphenols.

Abstract A combined experimental and computational study was developed to evaluate and understand the energetics and reactivity of formyl and methoxy a-naphthalene derivatives. Static bomb combustion calorimetry and the Calvet microcalorimetry were the experimental techniques used to determine the standard (p degrees = 0.1 MPa) molar enthalpies of formation, in the liquid phase, Delta H-f(m)o (1), and of vaporization, 4fH, at T= 298.15 K, respectively, of the two liquid naphthalene derivatives. Those experimental values were used to derive the values of the experimental standard molar enthalpies of formation, in the gaseous phase, Delta H-f(m)o(g), of 1-methoxynaphthalene, (-3.0 +/- 3.1) kJ mol(-1), and of 1-formylnaphthalene, (36.3 +/- 4.1) kJ mol(-1). High-level quantum chemical calculations at the composite G3(MP2)//B3LYP level were performed to estimate the values of the AfH(g) of the two compounds studied resulting in values in very good agreement with experimental ones. Natural bond orbital (NBO) calculations were also performed to determine more about the structure and reactivity of this class of compounds.

Abstract The standard (pA degrees A = 0.1 MPa) molar enthalpy of formation at T = 298.15 K for 4,5-dicyanoimidazole, in the crystalline phase, was derived from the standard molar energy of combustion measured by static bomb combustion calorimetry. This value and the literature value of the standard molar enthalpy of sublimation of the compound allow the calculation of the corresponding gas-phase standard molar enthalpy of formation, at T = 298.15 K. Additionally, theoretical calculations for 4,5-dicyanoimidazole were performed by density functional theory with the hybrid functional B3LYP and the 6-31G(d) basis set, extending the study to the 2,4- and 2,5-dicyanoimidazole isomers. Single-point energy calculations for both molecules were determined at the B3LYP/6-311+G(2df,2p) level of theory. With the objective of assessing the quality of the results, standard ab initio molecular orbital calculations at the G3 level were also performed. Enthalpies of formation, obtained using appropriate working reactions, were calculated and compared with the experimental data.

Abstract This work reports an experimental and computational thermochemical study of two aminothiazole derivatives, namely 2-aminothiazole and 2-aminobenzothiazole. The standard (p degrees =0.1 MPa) molar energies of combustion of these compounds were measured by rotating bomb combustion calorimetry. The standard molar enthalpies of sublimation, at T = 298.15 K, were derived from the temperature dependence of the vapor pressures of these compounds, measured by the Knudsen-effusion technique and from high temperature Calvet microcalorimetry. The conjugation of these experimental results enabled the calculation of the standard molar enthalpies of formation in the gaseous state, at T = 298.15 K, for the compounds studied. The corresponding standard Gibbs free energies of formation in crystalline and gaseous phases were also derived, allowing the analysis of their stability, in these phases. We have also estimated the gas-phase enthalpies of formation from high-level molecular orbital calculations at the G3(MP2)//B3LYP level of theory, the estimates revealing very good agreement with the experimental ones. The importance of some stabilizing electronic interactions occurring in the title molecules has been studied and quantitatively evaluated through Natural Bonding Orbital (NBO) of the corresponding wave-functions and their Nucleus Independent Chemical Shifts (NICS) parameters have been calculated in order to rationalize the effect of electronic delocalization upon stability.

Abstract Condensed phase standard (p degrees = 0.1 MPa) molar enthalpies of formation for 2-coumaranone and 3-coumaranone were derived from the standard molar enthalpies of combustion, in oxygen, at T = 298.15 K, measured by mini-bomb combustion calorimetry. Standard molar enthalpies of sublimation of both isomers were determined by Calvet microcalorimetry. These results were combined to derive the standard molar enthalpies of formation of the compounds, in gas phase, at T = 298.15 K. Additionally, accurate quantum chemical calculations have been performed using DFT methods and high level composite ab initio calculations. Theoretical estimates of the enthalpies of formation of the compounds are in good agreement with the experimental values thus supporting the predictions of the same parameters for isobenzofuranone, an isomer which has not been experimentally studied. The relative stability of these isomers has been evaluated by experimental and computational results. The importance of some stabilizing electronic intramolecular interactions has been studied and quantitatively evaluated through Natural Bonding Orbital (NBO) analysis of the wave functions and the nucleus independent chemical shift (NICS) of the studied systems have been calculated in order to study and establish the effect of electronic delocalization upon the relative stability of the isomers.

Abstract This study aims to investigate the effects of O-3 in protein content and immunoglobulin E (IgE)-binding profiles of Acer negundo, Platanus x acerifolia and Quercus robur pollen. Pollen was exposed to O-3 in an environmental chamber, at half, equal and four times the limit value for the human health protection in Europe. Pollen total soluble protein was determined with Coomassie Protein Assay Reagent, and the antigenic and allergenic properties were investigated by SDS-PAGE and immunological techniques using patients' sera. O-3 exposure affected total soluble protein content and some protein species within the SDS-PAGE protein profiles. Most of the sera revealed increased IgE reactivity to proteins of A. negundo and Q. robur pollen exposed to the pollutant compared with the non-exposed one, while the opposite was observed in P. x acerifolia pollen. So, the modifications seem to be species dependent, but do not necessarily imply that increase allergenicity would occur in atopic individuals.

Abstract The outcome of the Suzuki-Miyaura cross-coupling for the direct competition reaction between two boronic acids was evaluated under routine synthesis conditions. The reaction selectivity was found to depend on the amount of the base used, with fewer bases favoring the reactivity of the boronic acid with lower pK(a) (stronger acid). The dependence of the reaction selectivity on base stoichiometry was found to increase with the increase in the difference in the pK(a) values of the competing boronic acids. These results confirm a relationship between acid-base chemistry and the Suzuki-Miyaura reaction catalytic cycle. Moreover, the results indicate that under these specific conditions, the most reactive organoboron species toward transmetalation is the borate anion RB(OH)(3)(-) instead of the neutral boronic acid RB(OH)(2). Hence, the main role of the base in the reaction mechanism is to increase the reactivity of the boronic acid toward the Pd-halide complex by converting it into the respective organoborate. In addition, boric acid, an important reaction byproduct, affects the selectivity in the Suzuki reaction because its gradual formation in the reaction medium disturbs the acid-base equilibrium.