Wang_2023_J.Mol.Struct_1276_134804

Cholinesterase inhibition is a clinically validated therapeutic approach for treatment of Alzheimers disease (AD). A series of salicylic acid-based ChE inhibitors bearing carbamate group were designed and synthesized based on the principle of active substructure splicing. Among them, compounds 3l (IC50, eqBChE = 1.06 M, IC50, eeAChE = 2.08 M) and 3t (IC50, eqBChE = 0.82 M, IC50, eeAChE = 2.38 M) exhibited more potent dual AChE/BChE inhibitory activities compared with other compounds. Computational modeling results indicated that compounds 3l and 3t could bind to cholinesterase through hydrogen bonds and p-p stacking interactions. Moreover, they displayed potent neuroprotective properties and anti-apoptotic effects in mouse hippocampal HT22 cells. Importantly, the cell cytotoxicity and acute toxicity assays (1000 mg/kg) in mice confirmed that compounds 3l and 3t possessed an acceptable safety profile. The 3l and 3t were identified by the evaluation at the enzyme level and the cellular level, which are expected to be the privileged scaffolds for the development of dual AChE/BChE inhibitors