Conformationally locked 7-aryl tetrahydroisoquinolines as dual acetylcholinesterase inhibitors and antioxidants: role of intramolecular hydrogen bonding and aryl electronics.

Background: Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder in which cholinergic dysfunction and oxidative stress act as synergistic contributors to cognitive decline and neuronal damage. Multitarget-directed ligands (MTDLs) capable of modulating both acetylcholinesterase (AChE) activity and oxidative stress pathways are promising candidates for disease-modifying therapies. Methods: A series of conformationally locked 7-aryl tetrahydroisoquinoline derivatives was synthesized via a tandem cross-metathesis/Michael/annulation strategy. These compounds feature a stable intramolecular O-H···O=C hydrogen bond that enforces a quasi-planar geometry and modulates the electronic properties of the aryl substituent. The compounds were evaluated for their AChE inhibitory activity using Ellman's assay and for antioxidant capacity using the oxygen radical absorbance capacity (ORAC) assay. Molecular docking studies were performed to analyze binding modes within AChE's aromatic gorge, while density functional theory (DFT) calculations were conducted to assess the thermodynamics of hydrogen atom transfer (HAT) and ionization potential (IP) related to antioxidant behavior. Results: All derivatives exhibited micromolar AChE inhibition (IC Conclusion: This study identifies 7-aryl tetrahydroisoquinolines as a novel, mechanistically coherent scaffold for the development of dual-acting neuroprotective agents targeting both cholinergic dysfunction and oxidative stress in Alzheimer's disease. Their tunable electronic properties and preorganized geometry offer a promising foundation for further optimization within the multitarget therapeutic framework.