This is an author version of the contribution published on:Questa

Metal chelation is considered a rational therapeutic approach for interdicting Alzheimer's amyloid pathogenesis. At present, enhancing the targeting and efficacy of metal-ion chelating agents through ligand design is a main strategy in the development of the next generation of metal chelators. Inspired by the traditional dye Thioflavin-T, we have designed new multifunctional molecules that contain both amyloid binding and metal chelating properties. In silico techniques have enabled us to identify commercial compounds that enclose the designed molecular framework (M1), include potential antioxidant properties, facilitate the formation of iodine-labeled derivatives, and can be permeable through the blood-brain barrier. Iodination reactions of the selected compounds, 2-(2-hydroxyphenyl)benzoxazole (HBX), 2-(2-hydroxyphenyl)benzothiazole (HBT), and 2-(2-aminophenyl)-1H-benzimidazole (BM), have led to the corresponding iodinated derivatives HBXI, HBTI, and BMI, which have been characterized by X-ray diffraction. The chelating properties of the latter compounds toward Cu(II) and Zn(II) have been examined in the solid phase and in solution. The acidity constants of HBXI, HBTI, and BMI and the formation constants of the corresponding ML and ML2 complexes [M = Cu(II), Zn(II)] have been determined by UV-vis pH titrations. The calculated values for the overall formation constants for the ML2 complexes indicate the suitability of the HBXI, HBTI, and BMI ligands for sequestering Cu(II) and Zn(II) metal ions present in freshly prepared solutions of beta-amyloid (Abeta) peptide. This was confirmed by Abeta aggregation studies showing that these compounds are able to arrest the metal-promoted increase in amyloid fibril buildup. The fluorescence features of HBX, HBT, BM, and the corresponding iodinated derivatives, together with fluorescence microscopy studies on two types of pregrown fibrils, have shown that HBX and HBT compounds could behave as potential markers for the presence of amyloid fibrils, whereas HBXI and HBTI may be especially suitable for radioisotopic detection of Abeta deposits. Taken together, the results reported in this work show the potential of new multifunctional thioflavin-based chelating agents as Alzheimer's disease therapeutics.

In the denser and colder (≤20 K) regions of the interstellar medium (ISM), near-infrared observations have revealed the presence of submicron-sized dust grains covered by several layers of H2O-dominated ices and “dirtied” by the presence of other volatile species. Whether a molecule is in the gas or solid-phase depends on its binding energy (BE) on ice surfaces. Thus, BEs are crucial parameters for the astrochemical models that aim to reproduce the observed evolution of the ISM chemistry. In general, BEs can be inferred either from experimental techniques or by theoretical computations. In this work, we present a reliable computational methodology to evaluate the BEs of a large set (21) of astrochemical relevant species. We considered different periodic surface models of both crystalline and amorphous nature to mimic the interstellar water ice mantles. Both models ensure that hydrogen bond cooperativity is fully taken into account at variance with the small ice cluster models. Density functional theory adopting both B3LYP-D3 and M06-2X functionals was used to predict the species/ice structure and their BEs. As expected from the complexity of the ice surfaces, we found that each molecule can experience multiple BE values, which depend on its structure and position at the ice surface. A comparison of our computed data with literature data shows agreement in some cases and (large) differences in others. We discuss some astrophysical implications that show the importance of calculating BEs using more realistic interstellar ice surfaces to have reliable values for inclusion in the astrochemical models.

Interstellar formamide (NH 2 CHO) has recently attracted significant attention due to its potential role as a molecular building block in the formation of precursor biomolecules relevant for the origin of life. Its formation, whether on the surfaces of the interstellar forming more complex species, and can also act as catalysts by helping H transfer processes. Second, most of the involved intermediate steps towards formamide formation on the 33-H 2 O molecule cluster are so fast that it is unlikely that the energy released in each of them can be dispersed in the entire ice body of the grain. In other words, the system cannot be fully equilibrated at the grain temperature in each intermediate step, as assumed in all current models, because the localized energy can promote endothermic or high barrier processes in small portions of the ice before complete equilibration. The timescale of energy redistribution within the ice molecules, a poorly characterized process, should be explicitly accounted for if a realistic model of grain surface chemistry is pursued.

on a hydroxylated silica surface has been addressed by ab initio ONIOM2(B3LYP/6-311++G(d,p):MNDO) method within a cluster approach. A model cluster cut out from the (001) surface of an all-silica edingtonite terminated by silanol groups (2.2 OH nm -2 ) was used to simulate the surface. The adsorption process is mainly dictated by the hydrogen-bond (H-bond) interactions between both the COOH moiety and the side-chain functionalities of the considered AA and the terminal silanol groups of the surfaces. The computed adsorption energies were corrected for basis set superposition error and the role of dispersive interactions, not accounted for by the B3LYP functional, were estimated in a posterior fashion showing to be substantial for the adsorption free energies. Large AA and rich in hydrophilic functionalities in the lateral chain exhibit the most favorable adsorption energies because of the complementary role between dispersive interactions and H-bonds of medium strength with the silica surface. On the basis of the computed adsorption energies, an affinity scale of the considered AA for hydroxylated silica surface is established, which indicates that the nonpolar (Gly, Ala, Met, Phe) and the basic ones (His, Lys, Arg) are the least and the most prone to be adsorbed on the silica surface, respectively. Finally, assessments of the reliability of the structures obtained were performed by comparing the computed adsorption energies with experimental data related to the hydrophilic/hydrophobic character of the AA.