Ab initio design of chelating ligands relevant to Alzheimer's disease: influence of metalloaromaticity.

Evidence supporting the role of metal ions in Alzheimer's disease (AD) has rendered metal ion chelation as a promising therapeutic treatment. The rational design of efficient chelating ligands requires, however, a good knowledge of the electronic and molecular structure of the complexes formed. In the present work, the coordinative properties of a set of chelating ligands toward Cu(II) have been analyzed by means of DFT(B3LYP) calculations. Special attention has been paid to the aromatic behavior of the metalated rings of the complex and its influence on the chelating ability of the ligand. Ligands considered have identical metal binding sites (through N/O coordination) and only differ on the kind and size of the aromatic moieties. Results indicate that there is a good correlation between the stability constants (log beta(2)) and the degree of metalloaromaticity determined through the I-NG and HOMA indices; that is, the higher the metalloaromaticity, the larger the log beta(2) value. MOs and aromaticity descriptors confirm that present complexes exhibit Mobius metalloaromaticity. Detailed analysis of the nature of the Cu(II)-ligand bonding, performed through an energy decomposition analysis, indicates that ligands with less aromatic moieties have the negative charge more localized in the metalated ring, thus increasing their sigma-donor character and the metalloaromaticity of the complexes they form.