Multifunctional Ru(II)–Arene Complexes targeting Alzheimer's Disease: Antioxidant Activity, Amyloid-β Interactions, and Cholinesterase Inhibition

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder in which amyloid-β (Aβ) aggregation, oxidative stress, and cholinergic dysfunction play central roles. A series of hybrid coumarin-thiosemicarbazone ligands (L) and Ru(II)–arene complexes of general formula [Ru(p-cymene)Cl(P)] were synthesized, fully characterized, and evaluated as multifunctional agents for AD. Under the reaction conditions, L undergoes lactone ring opening and cyclization, yielding a pyrazolone-based ligand (P) at the metal center. Antioxidant capacity was assessed through four complementary approaches covering a broad range of radical species; complexes consistently outperformed their free ligands and conventional antioxidants. Metal–peptide interaction studies using imidazole as a histidine mimic provided evidence of Ru(II) coordination, and both complexes were found to modulate Aβ aggregation. Preliminary cholinesterase inhibition studies revealed dramatic AChE and BuChE inhibitory activity upon complexation. These results support the potential of [Ru(p-cymene)Cl(P)] complexes as multifunctional candidates for AD therapy.