Gomes_2025_Bioorg.Med.Chem_132_118447

BACKGROUND: Alzheimer's Disease (AD) is a progressive neurodegenerative disorder with no curative treatment available. Acetylcholinesterase (AChE) inhibition remains a validated approach for symptomatic management. Natural compounds such as carvacrol and selenium-based organochalcogenides are promising due to their antioxidant and neuroprotective properties. OBJECTIVES: This study aimed to design, synthesize, and evaluate twelve selenium-containing carvacrol derivatives as multifunctional anti-Alzheimer agents. METHODS: The compounds were synthesized via copper-catalyzed azide-alkyne cycloaddition (CuAAC), forming triazole-linked hybrids. Structural characterization was performed using NMR and HRMS. Biological evaluation included in vitro AChE inhibition assays (IC(50) determination), antioxidant profiling by cyclic voltammetry, and cytotoxicity screening. Computational studies involved molecular docking (GOLD software), DFT calculations, and ADMET predictions using pkCSM and SwissADME platforms. RESULTS: Compounds 18e and 18h showed the most potent AChE inhibition (IC(50) = 75 and 93 nM, respectively), exhibiting strong interactions with key residues such as Trp286 and Tyr341. Electrochemical assays identified 18l, 18f, and 18c as the most antioxidant derivatives, based on their low oxidation energy. ADMET predictions indicated high intestinal absorption (>95 %), BBB permeability, and no violations of Lipinski's rules. A strong correlation (R(2) = 0.9377) between docking scores and experimental IC(50) values supported the reliability of the in silico screening. CONCLUSION: The synthesized selenium-carvacrol hybrids exhibit a favorable combination of enzyme inhibition, antioxidant capacity, and pharmacokinetic properties. Compounds 18e and 18h demonstrated the most potential and represent valuable leads for future in-depth pharmacological studies and rational optimization in the context of Alzheimer's therapy.