Design, synthesis, biological activity and computational simulation evaluation of pyrimidine-2-aminoacetamide derivatives as cholinesterase inhibitors.

To search for novel anti-Alzheimer's disease candidate molecules, a series of pyrimidine-2-aminoacetamide derivatives were designed and synthesized, and their cholinesterase (ChE) inhibitory activities were systematically evaluated. The results showed that all target compounds exhibited varying degrees of inhibitory effects on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Among them, compound 17v had the most excellent activity, with IC50 values of 0.96 and 7.12 μM for AChE and BuChE, respectively, which were superior to the positive control galantamine (AChE: IC50 = 5.10 μM, BuChE: IC50 = 14.76 μM). In terms of antioxidant activity, the results indicated that the overall activity of all compounds was relatively weak, with the most active compound 17d having an IC50 value of 115.77 μM, which was inferior to ascorbic acid (IC50 = 41.17 μM). Molecular docking revealed that 17v binds to both catalytic and peripheral anionic sites of AChE, supporting a mixed-type inhibition mechanism confirmed by enzyme kinetics. A 100 ns molecular dynamics simulation confirmed stable binding of 17v within AChE and BuChE pockets. Target prediction and toxicity assessment suggested that compound 17v may possess multi-target neuroprotective potential and a favorable preliminary safety profile, supporting its further investigation as a potential therapeutic candidate for Alzheimer's disease. SwissADMET prediction indicated favorable physicochemical properties and drug-likeness profiles. In conclusion, compound 17v represents a promising lead compound for anti-Alzheimer's therapy.