Design and Studies of Multifunctional Hydroxypyridinone‐Based Biomimetic Chelators for Iron Coordination: A Density Functional Theory Approach

Abstract Hydroxypyridinones and their derivatives possess a wide spectrum of therapeutic applications, such as anti‐inflammatory, antifungal, antioxidant, anticancer, and others, and are used in chelation therapy. Anchoring more hydroxypyridinone units into a single ligand moiety can boost the chelating property of the latter due to the enhanced chelating effect and high thermodynamic stability. Saturation of the coordination sphere, charge, size, and topology are essential for the rational design of such molecules. Based on the above facts, in this study, four hydroxypyridinone‐based tripodal hexadentate cyclic chelators were designed and evaluated using computational tools. Their structural, spectroscopic, and binding properties with Fe(III) were analyzed to assess thermodynamic stability and coordination behavior. All ligands facilitate efficient Fe(III) encapsulation and the formation of hexadentate iron chelates with octahedral coordination, albeit with slight distortions. Natural bond order (NBO) analysis, energy decomposition analysis (EDA) via ETS‐NOCV, and global reactivity descriptors give insights into the nature of metal–ligand interactions. The study indicates the dominance of the electrostatic contributions over the covalent contributions, highlighting the predominantly ionic nature of Fe(III) complexation. Among the four ligands, the one that contains a 1,3,5‐cyclohexane central unit with an ethylene linker emerged as the most stable complex due to its optimal predisposition and preorganization. The stability of all the ligands considered in this study was compared based on various parameters.