Iraji_2025_BMC.Chem_19_97

Alzheimer's disease (AD) remains a significant public health challenge due to its progressive cognitive impairment and the absence of proven treatments. In this study, several novel 1,2,3-triazole-methoxyphenyl-1,3,4-oxadiazole derivatives were synthesized and evaluated for their ability to inhibit key enzymes associated with AD: acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Structure-activity relationship (SAR) analysis revealed that derivatives featuring electron-withdrawing groups, particularly nitro and fluorine substituents, exhibited remarkable inhibitory activity against BChE while showing minimal effectiveness against AChE. Among these, compound 13s (R = 4-CH(3), R' = 4-NO(2)) demonstrated the highest potency, selectively targeting BChE with an IC(50) value of 11.01 microM. Molecular docking and molecular dynamics (MD) simulations provided deeper insights into the favorable interactions between these compounds and BChE. Additionally, cytotoxicity studies confirmed the active compound's limited toxicity toward normal cells, indicating a promising therapeutic profile. These findings suggest that the synthesized selective anti-BChE compounds hold potential for consideration in the later stages of AD treatment.