ABSTRACT This study focuses on the strategic design of metallodrugs by precisely controlling their complex geometry and stability. We report the synthesis and comprehensive characterisation of a novel series of metal(II)–salen complexes derived from sterically hindered, brominated Schiff base ligands. Single‐crystal X‐ray diffraction analysis of a representative zinc complex confirmed that the bulky ligand framework enforces a rare, stable monomeric state with a distorted square‐pyramidal geometry, thereby preventing the typical dimerisation observed in such systems. The synthesised complexes demonstrate exceptional stability across a wide physiological pH range. Biological evaluation revealed that metal complexation significantly enhances the bioactivity of the complex. Notably, the Pd(II) complex emerged as a standout multifunctional therapeutic candidate, exhibiting potent broad‐spectrum antimicrobial activity, significant cytotoxicity against multiple human cancer cell lines and exceptional free‐radical scavenging capacity. In a complementary discovery, in silico molecular docking studies identified the free organic ligands themselves as potent acetylcholinesterase (AChE) inhibitors, with one ligand displaying binding affinity comparable to that of the established drug donepezil, suggesting their promise for neurodegenerative disease research. In simple terms, this work validates a ligand design strategy that stabilises monomeric metallodrug structures and identifies a highly active Pd(II) complex with triple‐action bioactivity. It also highlights the intrinsic medicinal potential of the organic scaffolds, presenting a dual‐pathway discovery of metal‐based and organic therapeutic leads.
Said et al. (2026) studied this question.