A systematic study of the thermodynamic stability of various Cu­(II) complexes with aminoguanidine (AG) is performed, together with the study of its secondary antioxidant activity. Calculations have been carried out at the M05­(SMD)/6-311+G­(d,p) level of theory using water as the solvent. The results obtained indicate that AG is capable of forming a wide array of stable coordination compounds with Cu­(II) under physiological pH conditions, and it possesses some degree of secondary antioxidant activity when coordinating to copper. The most thermodynamically stable complex can slow down 2.8 times the first step of the Haber–Weiss cycle (from 7.71 × 109 to 2.80 × 109 M–1 s–1) and slightly reduce the potential damage that the formation of •OH radicals can cause. The results of this research add to previous knowledge on this molecule, which could be used as a potential glycation inhibitor.

A thorough analysis of the thermodynamic stability of various complexes of aminoguanidine (AG) with Fe(III) at a physiological pH is presented. Moreover, the secondary antioxidant activity of AG is studied with respect to its kinetic role in the Fe(III) reduction to Fe(II) when reacting with the superoxide radical anion or ascorbate. Calculations are performed at the M05(SMD)/6-311+G(d,p) level of theory. Solvent effects (water) are taken into account in both geometry optimizations and frequency calculations employing the SMD solvation method. Even though the results of this study show that AG can form an extensive number of stable complexes with Fe(III), none of these can reduce the rate constant of the initial step of the Haber–Weiss cycle when the reducing agent is O2•−. However, when the reductant is the ascorbate anion, AG is capable of reducing the rate constant of this reaction significantly, to the point of inhibiting the production of •OH radicals. In fact, the most stable complex of Fe(III) with AG, having a ∆Gf° of −37.9 kcal/mol, can reduce the rate constant of this reaction by 7.9 × 105 times. Thus, AG possesses secondary antioxidant activity relative to the Fe(III)/Fe(II) reduction with ascorbate, but not with O2•−. Similar results have also been found for AG relative to the Cu(II)/Cu(I) reduction, in agreement with experimental results.

The thermodynamic stability of 11 complexes of Cu(II) and 26 complexes of Fe(III) is studied, comprising the ligands pyridoxamine (PM), ascorbic acid (ASC), and a model Amadori compound (AMD). In addition, the secondary antioxidant activity of PM is analyzed when chelating both Cu(II) and Fe(III), relative to the rate constant of the first step of the Haber-Weiss cycle, in the presence of the superoxide radical anion (O2•−) or ascorbate (ASC−). Calculations are performed at the M05(SMD)/6-311+G(d,p) level of theory. The aqueous environment is modeled by making use of the SMD solvation method in all calculations. This level of theory accurately reproduces the experimental data available. When put in perspective with the stability of various complexes of aminoguanidine (AG) (which we have previously studied), the following stability trends can be found for the Cu(II) and Fe(III) complexes, respectively: ASC < AG < AMD < PM and AG < ASC < AMD < PM. The most stable complex of Cu(II) with PM (with two bidentate ligands) presents a ΔGf0 value of −35.8 kcal/mol, whereas the Fe(III) complex with the highest stability (with three bidentate ligands) possesses a ΔGf0 of −58.9 kcal/mol. These complexes can significantly reduce the rate constant of the first step of the Haber-Weiss cycle with both O2•− and ASC−. In the case of the copper-containing reaction, the rates are reduced up to 9.70 × 103 and 4.09 × 1013 times, respectively. With iron, the rates become 1.78 × 103 and 4.45 × 1015 times smaller, respectively. Thus, PM presents significant secondary antioxidant activity since it is able to inhibit the production of ·OH radicals. This work concludes a series of studies on secondary antioxidant activity and allows potentially new glycation inhibitors to be investigated and compared relative to both PM and AG.