Ab Initio Design of Chelating Ligands Relevant to Alzheimer’s Disease: Influence of Metalloaromaticity

Abstract

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 β(2)) and the degree of metalloaromaticity determined through the I(NG) and HOMA indices; that is, the higher the metalloaromaticity, the larger the log β(2) value. MOs and aromaticity descriptors confirm that present complexes exhibit Möbius 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 σ-donor character and the metalloaromaticity of the complexes they form.

Electron Delocalization in Planar Metallacycles: Hückel or Möbius Aromatic?

“…But the situation becomes even more complicated in the case of planar d-metallaheterobicyclic aromatics like the one presented in Figure 5. According to the original report by Rimola et al, [27] this formally 16π system is regarded Möbius aromatic mainly due to significant equalization of the CÀ C, CÀ N, and CÀ O bond lengths (HOMA = 0.939), the normalized multicenter index [9c] being half as large as in benzene (I NG = 0.020), and characteristic shape of the lowest lying occupied π-MO. One should realize, however, that HOMO-15 is actually of Hückel type because here the copper atom does not allow cyclic delocalization to fall into opposite phase over a single cyclic unit.…”

“…[33] HOMA was calculated using only the CÀ C, CÀ N and CÀ O bonds and the calculationconsistent parameters from Ref. 6c (d-metallamonocycles) and the standard parameters provided by Krygowski et al [6b,27] The EDDBbased partition and orbital-decomposition were performed within the representation of natural atomic orbitals (NAO) [18] as implemented in the NBO 6.0 software [34] and the script program written by one of the authors (DS). [35] The corresponding EDDB(r) isosurfaces were generated by means of the standard tools from the Gaussian 09 package (Formchk and Cubegen).…”

How Reliable are Models Based on Topological Index 3χv for the Prediction of Stability Constants?

“…[22,23] The authors applied various theoretical methods on those systems, calculating stability constants of bis-complexes (log β 2) by DFT, along with HOMA and aromatic indices (ING), [22] but unfortunatelly they measured stability constants of only two of altogether ten complexes. [ [23] Linear correlation of DFT constants with 3 χ v index yielded S.E.= 0.85 and S.E.cv = 0.97 (r = 0.988) for all ten complexes. [24] However, thia-complexes could be regarded as a separate group and if they were discharged (N = 7), S.E.…”

The investigation of 2D monolayers as potential chelation agents in Alzheimer’s disease

“…Conclusions that were drawn regarding copper coordination to Aβ reveal that it occurs in the Histidine (His) 13 and 14 residues through their nitrogen atoms (Minicozzi et al (2008b); Curtain et al (2001); Mutter et al (2018); Streltsov et al (2008)) and N-terminal (Hane et al (2013); Syme et al (2004); Azimi and Rauk (2011); Rana and Sharma (2019)) along with contribution of one oxygen atom (Rimola et al (2011)). However, many theories of copper coordination were proposed and inconsistencies exist among the varying propositions.…”