In Silico Study, Synthesis, and In Vitro Evaluation of Nicotinamide-Substituted 1,3,5-Triazine Derivatives as Inhibitors of Acetylcholinesterase and Butyrylcholinesterase

In this study, a library of 138 hybrid nicotinamide-substituted 1,3,5-triazine compounds was designed using various heterocyclic moieties. From this library, ten compounds 4A (1, 8, 12, 14, 36, 38), 4B (37, 38), and 4C (21, 22) were selected through in silico screening, which included assessments of molecular properties, ADME profiles, toxicity predictions, and docking studies targeting the active sites of acetylcholinesterase (AChE, PDB ID: 1EVE) and butyrylcholinesterase (BChE, PDB ID: 4TPK). Docking results indicated that compounds 4A36 and 4A38 exhibited strong binding interactions with critical amino acids HIS440, GLY119, SER200, GLY118, ASP72, ASN85, TRP84 for AChE and TRP82, TRP430, TYR128, LEU286, TRP231, ALA328, PHE329 for BChE with binding affinities of -284.72 kcal/mol and -263.98 kcal/mol, respectively, comparable to the standard drug donepezil. The selected compounds were synthesized through conventional methods and characterized using various spectroscopic techniques. In vitro anti-cholinesterase activity evaluations revealed that compound 4A36 exhibited potent inhibition against AChE with IC50 value of 1.77 +/- 0.15 mu M and compound 4A38 exhibited moderate inhibition against BChE, with IC50 value of 4.80 +/- 0.62 mu M. These findings suggest that the hybrid scaffolds developed in this study hold significant potential for advancing the design of innovative therapeutic agents to treat Alzheimer's disease and related cognitive disorders.