Caruso_2025_Chem.Biol.Drug.Des_105_e70049

Alzheimer's disease is a neurodegenerative chronic disease with a severe social and economic impact in the societies, which still lacks an efficient therapy. Several pathophysiological events (beta-amyloid [Abeta] deposits, tau-protein aggregation, loss of cholinergic activity, and oxidative stress) occurs in the progression of the disease. Therefore, the search for efficient multi-targeted agents for the treatment of Alzheimer's disease becomes indispensable. In this paper we evaluated the AChE inhibition by Ellman's method and antioxidant activity by DPPH assay of nine synthetic compounds: two hydroxy-benzene derivatives (1 and 2), three bis-thioureidic derivatives (3-5), two imidazole derivatives (6 and 7), and two phenylacetamide derivatives (8 and 9). The compound 2, (3s,5s,7s)-adamantan-1-yl 4-(((E)-2,5-dihydroxybenzylidene)amino)benzoate, exhibited the best antioxidant activity (30.00 +/- 1.05 microM eq Trolox) and compound 4 showed the highest AChE inhibition value (IC(50) [microM] 8.40 +/- 0.32). In the search for a compound showing combined activities (antioxidant and AChE inhibition), the compound 4, octane-1,8-diyl-bis-S-amidinothiourea dihydrobromide, (19.02 +/- 1.52 microM eq Trolox; IC(50) [microM] 8.40 +/- 0.32) was chosen to carry out a molecular docking study. The results showed that compound 4 has the ability to bind the active site of acetylcholinesterase with considerable affinity (estimated binding energies of -8.5 kcal/mol). All data indicate that compound 4 has the potential to be further investigated as a possible candidate in the Alzheimer's disease treatment.