A computational study on the redox properties and binding affinities of iron complexes of hydroxypyridinones.

The potential of hydroxypyridinones for in vivo iron sequestration, in both biological and medical contexts, has been extensively discussed in the literature. Different chelators can be designed, with distinct lipophilicities that should alter their cell permeability, distribution, and rates of metabolism. However, for effective iron scavenging in biological systems, the redox potential and binding affinity of iron must fall within a proper range. Our objective was to assess the impact of different hydroxypyridinone chelators in 3:1 iron(III) complexes through comparison of these thermodynamic properties. For that purpose, we employed a cluster-continuum approach using density functional theory, on a dataset of 25 iron complexes. Whenever possible, our results were compared with experimental stability constants (log β) and with electrode potentials. We observed a good qualitative agreement between computed free energies of binding and log β values. In addition, we described which substitutions to the 3-hydroxypyridin-4-one ring should not markedly affect the redox properties and metal ion affinity considering iron. Graphical abstract Iron complexes of hydroxypyridinones.