Discovery of potent glycogen synthase kinase 3/cholinesterase inhibitors with neuroprotection as potential therapeutic agent for Alzheimer’s disease

[Display omitted] •A new series of AChE and GSK-3 dual inhibitors have been synthesized by fusing the pharmacophores of pyridothiazole with benzylpiperidine scaffold.•The most promising hybrid GD29 shows favorable kinase selectivity profiles.•Hybrids exhibited anti-inflammatory properties and neuroprotective profiles.•Compound GD29 showed good BBB permeability and pharmacokinetic properties. In the present work, a novel series of pyridinethiazole bearing benzylpiperidine hybrids were designed and synthesized as dual-target inhibitors of GSK-3β/AChE. Among them, GD29 was the most promising candidate, with an IC50 value of 0.3 μM for hAChE and an IC50 value of 0.003 μM for hGSK-3β, respectively. The compounds exhibited good drug-like properties with optimal inhibitory enzyme activities. Moreover, GD29 showed anti-inflammatory properties at micromolar concentrations and displayed interesting neuroprotective profiles in an in vitro model of oxidative stress-induced neuronal death. Notably, the compounds also exhibited good permeability across the blood–brain-barrier (BBB) both in vitro. Central cholinomimetic activity was confirmed using a scopolamine-induced cognition impairment model in Institute of Cancer Research (ICR) mice upon oral administration. The current work identified optimized compounds and explored the therapeutic potential of glycogen synthase kinase 3/cholinesterase inhibition for the treatment of AD.