Shaaban_2025_Arch.Pharm.(Weinheim)_358_e70035

Alzheimer's disease (AD) is a complex neurological disorder that arises from multiple factors. The innovative multitarget-directed ligand (MTDL) approach, which incorporates multiple pharmacophores into one molecule, enhances the development of effective therapeutics for AD. Eighteen novel natural product-based purine MTDLs were synthesized. These hybrids were evaluated In Vitro for their inhibitory effects on AChE, BChE, MAO-A, and MAO-B. The findings revealed that most hybrids effectively and selectively inhibited AChE. Hybrid 9b demonstrated the highest inhibitory potency against AChE, BChE, MAO-A, and MAO-B, exhibiting IC(50) values of 5.52, 11.64, 25.99, and 34.78 microM, respectively. In addition, hybrid 9b exhibited interesting antioxidant activity, with an IC(50) of 6.69 microM. The mechanism of action and the binding modes of hybrid 9b were analyzed through molecular docking studies. Molecular dynamics simulation revealed that hybrid 9b is stable within the AChE active site. In Silico assessments of physicochemical properties for hybrid 9b indicate that it is well absorbed following oral administration and can penetrate brain tissue. Finally, hybrid 9b stability studies in simulated gastric and intestinal conditions suggested that it could be absorbed into the bloodstream without significant degradation. Consequently, these findings reinforce the potential therapeutic applications of hybrid 9b as a multifunctional therapeutic candidate for addressing AD.