Theoretical Study of Copper(II) Coordination Complexes with Coumarin-Derived Heterocyclic Ligands Through DFT and CDFT

Copper(II) coordination complexes with coumarin-derived heterocyclic ligands are promising in inorganic therapeutics for anticancer and antimicrobial applications. To establish quantitative structure–activity relationships for lead design, we studied six copper(II) complexes (Cu1–Cu6)with four- and five-coordinate geometries using Density Functional Theory, Conceptual Density Functional Theory, and visualization analyses. Geometry optimization at M06/6-31G(d)+DZVP revealed distorted coordination environments from d9 Jahn–Teller effects. Tridentate N2O-chelatedcomplexes (Cu4–Cu6) showed greater aqueous stability (ΔGsolv=−43 to −50 kcal·mol−1) than four-coordinate analogs (−29 to −31 kcal·mol−1). CDFT global descriptors contrasted reactivity: four-coordinate Cu1–Cu2 had higher electron affinity (>4.2 eV) and electrophilicity (>5.7 eV), suggesting propensity for redox cycling and for undergoing nucleophilic attack by DNA bases, whereas Cu4–Cu6 displayed increased chemical hardness (3.43–3.54 eV) and lower electrophilicity (≈3.8 eV), implying enhanced kinetic stability and bioavailability. Frontier orbital analysis indicated ligand-to-metal charge transfer via a LUMO delocalized over the π-conjugated coumarin, facilitating intercalation by π-π stacking. The visualization showed strong covalent bonds (blue isosurfaces) stabilizing the metal and dispersive π interactions (green surfaces) on the ligand, enabling solvent interactions and biomolecular recognition. Tridentate N2O coordination thus balances electronic stability and biological reactivity, making Cu4–Cu6 promising for further study.