Discovery of novel β-carboline-1,2,3-triazole hybrids as AChE/GSK-3β dual inhibitors for Alzheimer's disease treatment.

Alzheimer's disease (AD) is characterized by progressive cognitive impairment and mental behavior. The combination inhibition of two essential AD targets, acetylcholinesterase (AChE) and glycogen synthase kinase-3β (GSK-3β), might be a breakthrough in the discovery of therapeutic success. Herein, 17 β-carboline-1,2,3-triazole hybrids were designed, synthesized, and evaluated for their AChE and GSK-3β inhibitory potential. The results indicated that compound 21 has the most potent inhibition against eeAChE (IC = 0.20 ± 0.02 μM), hAChE (IC = 0.34 ± 0.01 μM) and GSK-3β (IC = 1.14 ± 0.05 μM) among these compounds. In addition, it inhibited hAChE in a mixed type manner and could occupy the binding pocket forming diverse interactions with the target of AChE and GSK-3β. Moreover, compound 21 showed low cytotoxicity against SH-SY5Y and HepG2 cell lines and good BBB permeability. Compound 21 also attenuated the tau hyperphosphorylation in the Tau (P301L) 293T cell model. The ADME projection exhibited that compound 21 has acceptable physicochemical characteristics. This study provides new leads for the assessment of AChE and GSK-3β dual inhibition as a promising strategy for AD treatment.