Kuyrukcu_2025_Bioorg.Med.Chem_132_118445

Alzheimer's disease (AD) is a neurodegenerative disorder and acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and sphingomyelinase (SMase) enzymes are among its therapeutic targets. In this study, a series of tetrahydropyrimidine and hexahydropyrimidine derivatives were synthesized and evaluated for their inhibition of Bacillus cereus SMase, electric eel AChE (EeAChE), and equine BuChE (eqBuChE) as potential agents against AD. Among the synthesized compounds, 4-oxo-6-(pyridin-2-yl)-2-thioxohexahydropyrimidine-5carbonitrile (compound 24) was found to be the most active compound against B. cereus SMase, with an IC(50) value of 1.61 microM. In addition, 2-(benzylthio)-4-octyl-6-oxo-1,6-dihydropyrimidine-5carbonitrile (compound 14) and 4-octyl-6-oxo-2-(phenethylthio)-1,6-dihydropyrimidine-5carbonitrile (compound 16) exhibited selective eqBuChE inhibition with IC(50) values of 3.68 and 1.65 microM, respectively. The mode of inhibition of the selected compounds was determined by enzyme kinetic study. These compounds were also examined for their metal-chelating properties with various biometals and effect of B. cereus-induced hemolysis on sheep erythrocytes. Additionally, compound 24 showed no cytotoxic effect on the HUVEC cell line at its IC(50) concentration. The biological data were supported by the results of molecular docking studies, and in-silico physicochemical properties/ADME predictions of the selected compounds were determined.