Abstract

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 & centerdot;& centerdot;& centerdot;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 (IC50 = 33-54 & micro;M), with structure-activity relationships driven by the electronic nature and pi-polarizability of the 7-aryl ring. Docking results revealed a conserved, pi-dominated binding pose within the enzyme's active site. ORAC measurements showed substituent-dependent radical-scavenging activity consistent with the electronic trends observed in enzyme inhibition. DFT calculations indicated a thermodynamic preference for hydrogen atom transfer (HAT) from benzylic C-H over phenolic O-H cleavage, supporting the observed antioxidant profile.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.