Synthesis, structural characterization and molecular docking analysis of novel β-ketoiminato palladium(ii) complexes...

A novel series of palladium(ii) coordination complexes of the formula [Pd(CH₃C(NAr)CHC(O)CH₃)₂] (4a-j) were synthesized by the reaction of enaminone ligands (3a-j) with [PdCl₂(NCCH₃)₂] in a molar ratio of 2 : 1 in the presence of ^t BuOK. The square planar coordination geometry around Pd(ii) of the 4c complex, with electrostatic potential calculations rationalizing the formation of C-H⋯π contacts, leading to chain structures, was confirmed by single-crystal X-ray diffraction. UV-vis spectra, supported by TD-DFT (B3LYP) calculations, indicated that the long-wavelength absorptions arose from intra-ligand charge transfer transitions (π → π*) involving HOMO-LUMO+1 excitations, with Pd(ii) orbitals contributing to the HOMO. Thermogravimetric analysis demonstrated high thermal stability of the series. Biological evaluation revealed notable cytotoxicities of the compounds 4b, 4d, 4h, 4i, and 4j. The compound 4i shows the strongest activity (IC₅₀ = 5.42 µM, MCF-7; 17.20 µM, and HCT-116) and high selectivity toward cancer cells. Molecular docking against oncogenic targets (PIK3CA-E545K, ERBB4-Y1242C, KRAS-G13D, PIK3CA-H1047R, and ATM-A112V) identified meta- and para-substituted analogues (4b, 4c, and 4h) as the most favorable binders, while bulky ortho substituents reduced the affinity due to steric effects. Docking against PIK3CA-E545K produced binding energies that qualitatively paralleled several of the measured MCF-7 selectivity indices, with planar aromatic interactions and hydrophobic contacts defining the structure-activity relationships.