The chelating agents for Al3+ and Fe3+ metal cations with therapeutic applications have been considered in the recent years. In designing of the hydroxypyridinones (HPOs) as the therapeutic chelating agents for iron and aluminium overload pathologies, quantum mechanical (QM) calculations are necessary for predicting the binding energies and thermodynamic parameters of the metal-HPO complexes. Three derivatives of the HPOs called 3-hydroxy-1,2-dimethylpyridin-4(1H)-one (DFP), 3-hydroxy-4(1H)-pyridinone (HOPO) and 5-hydroxy-2-(hydroxymethyl)pyridin-4(1H)-one (P1) were investigated for complexation with Fe3+ and Al3+ metal ions. Because of the maximum interaction between Fe3+ and HPOs, all HPOs form stable complexes with Fe3+ metal ion. Moreover, it was found that [Fe-P1]2+ is a more stable complex than [Fe-DFP]2+ and [Fe-3,4-HOPO]2+ in the gas phase and water, confirming that P1 is the strongest selective iron chelator. The more stability of [Fe-P1]2+ was attributed to an intramolecular hydrogen bond formation between the hydrogen atom of -NH- group and the oxygen atom of -CH2OH chain. All complexes of the HPOs with Fe3+ and Al3+ were formed through the oxygen atoms of the C=O and O-H groups of the HPO. Natural bond orbital analysis showed that the interaction of the lone pair electrons of the oxygen atom of the chelator and antibonding orbitals of the Al3+ and Fe3+ are important in the complex formation. Topological parameters at the bond critical points confirmed the effective interaction between the Al3+ and Fe3+ metal ions and HPO as well as the nature of the metal-oxygen bonds.

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