Design, synthesis, and in vitro evaluation of novel longifolene derivatives for Alzheimer's disease.

AIM: The study combines computational and experimental approaches to provide structural and functional features of novel ligands, emphasizing their promising role as canditates for Alzheimer's disease (AD) drug development. MATERIALS AND METHODS: The research focused on developing molecules capable of targeting acetylcholinesterase (AChE) enzyme as potential treatments for AD. Starting with longifolene, a natural compound known for its anti-inflammatory properties, 198 derivatives were designed. Structure-guided molecular docking, MD simulations, and MM/GBSA free energy calculations identified four compounds that exhibited favorable interactions on AChE. These compounds were synthesized and characterized, followed by series of biological evaluation. Donepezil hydrochloride was used as the standard reference drug. RESULTS: Cytotoxicity assay conducted established its safety on SH-SY5Y cells with IC50 exceeding 90 µM. In the in vitro model developed for AD using Aβ1-42, the ligands demonstrated anti-inflammatory and neuroprotective effects with compound 4f showing promising effect. At 0.1 and 0.3 µM, compound 4f significantly decreased intracellular reactive oxygen species, preserved mitochondrial membrane potential, and reduced cellular apoptosis. CONCLUSIONS: The results identify compound 4f as a promising lead candidate for AD management. The molecular hybridization strategy successfully enhances biological activity, supporting further preclinical development of longifolene-derived scaffolds as potential anti-Alzheimer's therapeutics.