Metal‐ and Spacer‐Guided Biomolecular Interactions of Closed‐Shell Ni(II), Pd(II), Zn(II) and Cd(II) Schiff Base Complexes

ABSTRACT The present study focused on the synthesis, characterization and DNA‐binding studies of four closed‐shell tetradentate Ni(II) ( 1 ), Zn(II) ( 2 ), Cd(II) ( 3 ) and Pd(II) ( 4 ) Schiff base complexes derived from 3‐ethoxysalicylaldehyde. Through this work, we probe the effect of metal‐induced geometry ( d 8 planar vs. d 10 distorted) and diimine spacer flexibility (conjugated aromatic vs. insulating aliphatic) on biomolecular target selectivity. The complexes ( 1 – 4 ) were synthesized and characterized via various spectroscopic and SCXRD analyses. Computational density functional theory (DFT) and solvatochromic studies were conducted, and the experimental DNA‐binding interactions were probed via absorption titration and docking methods. SCXRD and spectral analyses confirmed near‐ideal square‐planar coordination cores for 1 ( τ 4 = 0.08) and 4 ( τ 4 = 0.101), whereas the closed‐shell d 10 Zn ( 2 ) and Cd ( 3 ) centres experienced noticeable spatial distortions. Spectroscopic CT‐DNA‐binding titrations revealed an interaction order of 1 > 4 > 2 > 3 , revealing that planar, d 8 cores exhibit superior DNA binding ( K b = 3.12 × 10 5 M −1 for 1 ). DFT studies at the PBE0/def2‐SVP/GD3BJ level reveal that the aromatic o ‐phenylenediamine spacer in 1 results in a narrow energy gap (Δ E = 2.92 eV), high global softness ( S = 0.342 eV −1 ) and maximum electrophilicity ( ω = 4.51 eV) and results in high electronic polarizability that facilitates close non‐covalent association and terminal‐site stacking along the electron‐rich DNA interface. Conversely, the aliphatic sp 3 ‐hybridized 2,2‐dimethyl‐1,3‐diamino spacer in 4 removes spacer conjugation, resulting in higher electronic hardness (Δ E = 3.29 eV, η = 1.645 eV) and facilitating structural adaptation to target active sites. Molecular docking studies corroborate these mechanisms, demonstrating that the planar systems ( 1 and 4 ) engage B‐DNA most closely, docking at the terminal base‐pair/backbone interface rather than the duplex interior. Among these, 4 exhibits the strongest affinity towards the ATP‐binding pocket of EGFR kinase facilitated by various non‐covalent interactions. These results show that the selection of metal centre and spacer backbone tunes DNA backbone/terminal‐site engagement versus kinase pocket targeting in metal‐based anticancer drug design.