Novel 1,2,4-triazole derivatives containing the naphthalene moiety as selective butyrylcholinesterase inhibitors: Design, synthesis, and biological evaluation

Butyrylcholinesterase (BChE) is considered a promising therapeutic target for treating Alzheimer's disease due to the increase in the levels and activity of BChE in the late stage of the disease. In this study, a series of novel 1,2,4-triazole derivatives bearing the naphthalene moiety linked to the benzothiazole, thiazole, and phenyl scaffolds via amid chain were designed and synthesized as potential and selective BChE inhibitors. The results of the inhibitory activity studies revealed that most of these compounds exhibited significant inhibitor potency on BChE. Compounds 35a (0.025 ± 0.01 μM) and 37a (0.035 ± 0.01 μM) displayed the most potent inhibitory activity, with excellent selectivity against BChE over acetylcholinesterase (SI_BChE, 23,686 and 16,936, respectively) among the target compounds. The kinetics studies revealed that these compounds behaved with noncompetitive BChE inhibitors. Molecular docking studies indicated that 35a and 37a fit well into the active side of BChE. In addition, 35a and 37a also had the lowest cytotoxicity for human neuroblastoma cells (SH-SY5Y), potential antioxidant capacity, moderate inhibition potency on amyloid-β_1-42 aggregation, and significant neuroprotective effect against SH-SY5Y cell injury induced by H₂O₂ and amyloid-β_1-42. All results suggest that these compounds might be considered as promising new lead compounds in the drug discovery process for the treatment of late-stage Alzheimer's disease.