N-substituted thiourea derivatives based aminoalcohols: Discovery of potent cholinesterase inhibitors as new therapeutic approach In Alzheimer’s disease

A novel series of aminoalcohol-based N-substituted thiourea derivatives ( T1–T5 ) were synthesized and systematically evaluated as potential acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors. The structures of the synthesized compounds were elucidated using 1 H and 13 C NMR spectroscopies. In vitro enzyme inhibition studies revealed that all derivatives exhibited significant cholinesterase inhibitory effect at the nanomolar level. Among these, compound T3 , bearing an electron-donating isopropylamino substituent, emerged as the most potent double inhibitor, exhibiting Kᵢ values of 43.57 ± 5.52 nM for AChE and 90.03 ± 8.33 nM for BChE. To rationalize the experimental findings, structure-based molecular docking studies ( in silico applications) were performed against human AChE and BChE. The docking results showed strong agreement with in vitro data; compound T3 exhibited optimal binding affinities (-9.6 Kcal/mol for AChE and −9.0 Kcal/mol for BChE) and stable interaction patterns involving both catalytic and peripheral site residues. Structure-activity relationship analysis showed that electron-donating N-substituents and the flexible aminoalcohol-thiourea skeleton played a significant role in enhancing the inhibitory potential. Overall, the combined experimental and computational results identify compound T3 as a promising dual AChE/BChE inhibitor and highlight aminoalcohol-based N-substituted thioureas as a valuable skeleton for further optimization in Alzheimer's disease-related drug discovery.