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

Abstract

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 1H and 13C 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 K-i 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.