Crystal structure and cholinesterase inhibition investigations of copper complexes of pyrazine-modulated tripyridyldiamine: a computational and experimental method

Abstract

The pyrazine-modulated oligo-α-pyridylamino ligand N,N′-di(pyrazin-2-yl)pyridine−2,6-diamine (H₂dpzpda) was used to synthesize and structurally characterize two novel mononuclear copper(II) complexes. In both complexes, H₂dpzpda acts as a tridentate ligand and coordinates to the metal center in an all-anti conformation. Complex 1 exhibits a distorted trigonal–bipyramidal geometry around the Cu(II) center, whereas complex 2 adopts a distorted square-pyramidal geometry. The nitrogen atoms of the amino groups remain uncoordinated in both complexes. The free ligand and its copper(II) complexes were evaluated as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors. The free H₂dpzpda ligand exhibited IC₅₀ values of 9.83 and 50.72 µM against AChE and BChE, respectively. Complexes 1 and 2 displayed IC₅₀ values of 5.50 and 1.42 µM against AChE and 41.30 and 25.68 µM against BChE, respectively. Comparison with the free ligand demonstrated that Cu(II) coordination enhanced cholinesterase inhibitory activity, particularly for complex 2 against AChE. Molecular docking and molecular dynamics simulations were also performed for both complexes against the two enzymes. In addition to single-crystal X-ray diffraction analyses, Hirshfeld surface analysis and two-dimensional fingerprint plots were employed to investigate the intermolecular interactions within the crystal structures. Furthermore, DFT calculations revealed HOMO–LUMO energy gaps of 3.70 and 0.79 eV for complexes 1 and 2, respectively. The markedly smaller energy gap of complex 2 indicated greater frontier-orbital delocalization and a higher tendency toward electronic transitions, while the molecular electrostatic potential maps identified the chloride, nitrate oxygen, and pyrazine nitrogen atoms as the principal electron-rich regions. These theoretical findings supported the structural and electronic features observed experimentally.