Salophen-Type ONNO Donor Schiff Base and Its Mn(II), Fe(II), Ni(II), and Cu(II) Complexes: Synthesis, Characterization, Cytotoxic Activity, Quantum Chemical Calculation, and Molecular Modeling Investigation

Abstract

The ligand 2-((2-(3-tert-butyl-2-hydroxybenzylideneamino)phenylimino)methyl)-6-tert-butylphenol (H<inf>2</inf>L) was synthesized by the condensation reaction of 1,2-phenylenediamine and 3-tert-butyl-salicylaldehyde. Metal(II) complexes of the H<inf>2</inf>L were obtained using a 1:1 reaction between the H<inf>2</inf>L and M(OAc)<inf>2</inf> (M: Mn, Fe, Ni, and Cu). Salophen-type ligand and metal(II) complexes were characterized using UV–Vis, FT-IR, NMR spectroscopy, elemental analysis, magnetic susceptibility, and molar conductivity measurements. The optimized molecular geometries, frontier molecular orbitals (FMOs), molecular electrostatic potential (MEP) diagrams, and total density of states of both H<inf>2</inf>L and its corresponding complexes were calculated at the DFT/B3LYP level using the LANL2DZ basis set for metal(II) ions and 6-311G(d,p) for other atoms. Spectroscopic analyses and quantum chemical calculations confirmed the formation of a four-coordinated square-planar geometry of the metal(II) complexes. The cytotoxic activities of the H<inf>2</inf>L and its complexes were evaluated in MDA-MB-231 and HepG2 cancer cell lines. Among the tested compounds, the MnL demonstrated the highest cytotoxicity, with IC<inf>50</inf> values of 32.80 and 16.96 μM for the MDA-MB-231 and HepG2 cell lines, respectively. The MnL complex showed nearly 10-fold higher cytotoxicity than CuL and FeL in HepG2 cells and more than fivefold in MDA-MB-231, clearly indicating the critical role of metal ion selection. Furthermore, quantum chemical calculations revealed that metal(II) complexation significantly reduced the HOMO/SOMO–LUMO energy gap (ΔE), enhancing the reactivity of the compounds. The NiL complex had the lowest energy gap (0.872 eV), indicating the highest softness, whereas the H<inf>2</inf>L showed the highest gap (3.902 eV), suggesting superior stability but lower reactivity. Molecular docking studies against VEGFR2 (PDB ID: 2XIR) indicated that the H<inf>2</inf>L exhibited the highest binding affinity (−9.9 kcal/mol), followed by the MnL complex (−9.1 kcal/mol). Moreover, a molecular dynamics simulation performed for 100 ns confirmed the stability of the MnL–2XIR complex under physiological conditions. The RMSD and Rg values remained highly stable throughout the simulation, supporting a tight and persistent binding mode. These findings indicate that the MnL complex has potential as an anticancer agent and needs further investigation. Notably, this study is among the few comprehensive investigations that combine synthesis, cytotoxicity evaluation, quantum chemical analysis, molecular docking, and long-timescale molecular dynamics simulation of salophen-type Mn(II) complexes. © 2025 Elsevier B.V., All rights reserved.