Structure-Based Design of Chiral Thioureas as Anticholinesterase Inhibitors Using Enantiopure α-Methylbenzylamines: Synthesis, Enzyme Inhibition, and In Silico Studies

Abstract

A detailed analysis of the research on the treatment of Alzheimer's disease indicates that selective inhibition of butyrylcholinesterase (BChE) is the most promising strategy for identifying a drug target. According to this perspective, in this study, a new series of potential BChE inhibitors (1a–8a and 1b–8b) were designed using a structure-based design approach and synthesized as enantiomer pairs based on the benzyl thiourea attached to a chiral moiety. The in vitro anticholinesterase activity studies against acetylcholinesterase (AChE) and BChE consistently demonstrated that the majority of the designed compounds exhibited selective and potent BChE inhibition. Also, the present results of the study reveal that compound 6b, which has a methyl group at the para position of the phenyl ring and has an S configuration, was the most potent compound against BChE with an IC₅₀ value of 1.46 ± 1.99 μM (SI = 8.47). In contrast, the chiral thioureas (8a and 8b) bearing a cyclohexyl group demonstrated higher selectivity toward AChE, with SI values of 2.10 and 2.32, respectively. Notably, compounds 2a and 2b showed dual inhibitory effects with similar potency for AChE and greater potency for BChE, compared to the standard drug galantamine. The molecular docking method, which showed a good correlation with our in vitro anticholinesterase activity results, was used to predict the interactions of all chiral thioureas within the binding pockets of AChE and BChE. Further structural improvement of these molecules in future studies may lead to the emergence of more potent AChE and BChE inhibitors.