Pyrimidine derivatives with cholinesterase inhibitory, anticonvulsant, and anticancer activities evaluated through experimental and computational studies

A series of pyrimidine derivatives ( 1–12 ) was synthesized and investigated as multifunctional bioactive molecules based on their promising molecular docking profiles against cholinesterase targets, which provided the rationale for subsequent biological evaluation. The synthesized compounds were evaluated for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition, anticonvulsant activity, anticancer potential, and computational characteristics. Among the tested compounds, compound 4 exhibited the highest cholinesterase inhibitory activity with IC 50 values of 0.70 ± 0.03 µM (AChE) and 2.90 ± 0.12 µM (BChE), while compounds 1 , 2 , 9 , and 11 also showed potent dual enzyme inhibition (AChE IC 50 = 0.95–1.60 µM; BChE IC 50 = 3.60–4.20 µM). In vivo anticonvulsant studies demonstrated that compound 4 produced the greatest seizure protection, achieving 83% protection in the maximal electroshock seizure (MES) model and 85% protection in the pentylenetetrazole (PTZ) model at 20 mg/kg, whereas compounds 1 , 2 , 9 , and 11 also exhibited pronounced dose-dependent anticonvulsant effects. In cytotoxicity studies, compounds 2 and 11 displayed selective antiproliferative activity against SH-SY5Y neuroblastoma cells with IC 50 values of 45.6 and 46.3 µM, respectively, while exhibiting comparatively low toxicity toward normal neuronal cells. Molecular docking demonstrated favorable binding of the lead compounds within the active sites of AChE and BChE through multiple hydrogen-bonding and hydrophobic interactions, supporting the observed experimental activities. Hence, the combined computational and experimental findings identify compounds 2 , 4 , and 11 as promising lead pyrimidine derivatives for further optimization as multifunctional agents targeting cholinesterase-associated neurological disorders with additional selective anticancer potential.