Sustainable synthesis and biological evaluation of tacrine-like multi-target hybrids as anti-Alzheimer candidates

The complex and multifactorial etiology of Alzheimer’s disease (AD) imposes a severe socioeconomic burden and highlights the limitations of current therapeutic options, which are mainly confined to symptomatic drugs or monoclonal antibody-based therapies with restricted eligibility and relevant adverse effects. To overcome these limitations and address the multiple pathways involved in neurodegeneration, the development of multi-target-directed ligands (MTDLs) has emerged as a key paradigm in modern drug discovery. In this framework, we report the design and synthesis of a novel library of MTDL hybrids combining a tacrine core, selected for its well-established anticholinesterase properties, with bioactive aryloxy-methylene scaffolds. Although initial synthetic efforts relied on conventional procedures, the methodology was successfully re-engineered according to green chemistry principles. In particular, the use of deep eutectic solvents (DESs) markedly improved reaction efficiency and sustainability, aligning the synthetic workflow with eco-friendly standards. In vitro enzymatic screening demonstrated that all synthesized derivatives exerted potent dual inhibition against both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Furthermore, structure–activity relationship (SAR) analysis revealed that the electronic and steric features of the substituents on the aryloxy ring critically modulate both inhibitory potency and selectivity.