Nowadays, 3-hydroxypyridine-4-ones (HPOs) as orally active iron chelators have been introduced for the treatment of disorders associated with iron such as iron overload in thalassemia patients. In this work, a density functional theory (DFT) study was performed on a series of HPOs constituted of the different substitutions at the different positions. Structural analysis indicates that all of the HPO derivatives bind to Fe3+ as a two-dentate mode through the oxygen atoms of the C==O groups. It is confirmed that the HPO derivative composed of three methyl groups at the different positions (3-hydroxy-1,2,5-trimethyl-4(1H) pyridinone) forms the most stable complex with Fe3+. Therefore, this HPO derivative acts as a better iron chelator than other ones. The vibrational frequency analysis reveals a correlation between the iron affinity constant and C==O vibrational frequency of the HPOs. Donor-acceptor interactions show an effective charge transfer from the oxygen atoms of the HPOs towards Fe3+. Quantum theory of atoms in molecules analysis shows the non-covalent interactions, mainly, electrostatic interactions play an important role in the complex formation of the HPOs and Fe3+. Finally, some linear correlations between the electron densities of the Fe−−O chemical bond and interaction energy values, the vibrational frequency of the C==O bonds and electron densities of the Fe−−O chemical bond were obtained and analyzed.

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