Design, structural elucidation, and multi-target enzyme inhibition of pyrazolidine-based Cu(II) and Ni(II) complexes: integrated experimental, DFT, and docking insights

Schiff base transition-metal complexes are promising multifunctional scaffolds because metal coordination can regulate molecular geometry, electronic structure, and enzyme-binding behavior. This study aimed to synthesize pyrazolidine-based Cu(II) and Ni(II) complexes and clarify the role of metal coordination in their structural, theoretical, and multi-target enzyme inhibition profiles. The ligand and its Cu(II)-L and Ni(II)-L complexes were characterized by elemental analysis, FT-IR, UV–Vis, HPLC-PDA, and single-crystal X-ray diffraction, supported by Density functional theory (DFT), Quantum Theory of Atoms in Molecules (QTAIM), Hirshfeld surface analysis, and molecular docking/redocking. X-ray analysis revealed marked ligand reorganization after coordination, with Cu(II)-L showing a distorted coordination environment and Ni(II)-L a more symmetric square-planar geometry. DFT calculations gave HOMO–LUMO gaps of 1.78 eV for Cu(II)-L and 3.27 eV for Ni(II)-L, indicating higher reactivity for Cu(II)-L. Enzyme assays showed that Cu(II)-L was the most potent inhibitor of hCA I and AChE, with Ki values of 3.22 ± 0.60 μM and 4.78 ± 0.61 μM, respectively. Cu(II)-L and the free ligand exhibited comparable hCA II inhibition (4.50 ± 1.28 and 4.72 ± 1.35 μM), whereas the free ligand showed the strongest BChE inhibition (2.38 ± 0.10 μM). Docking results reproduced the experimental trends, with redocking RMSD values of 1.98, 1.96, 0.65, and 2.49 Å for hCA I, hCA II, AChE, and BChE, respectively. Overall, Cu(II) coordination enhances hCA I and AChE inhibition, while ligand flexibility favors BChE activity.