Discovery of Novel Tacrine–Pyrimidone Hybrids as Potent Dual AChE/GSK‑3 Inhibitors for the Treatment of Alzheimer’s Disease

Based
on a multitarget strategy, a series of novel tacrine–pyrimidone
hybrids were identified for the potential treatment of Alzheimer’s
disease (AD). Biological evaluation results demonstrated that these
hybrids exhibited significant inhibitory activities toward acetylcholinesterase
(AChE) and glycogen synthase kinase 3 (GSK-3). The optimal compound 27g possessed excellent dual AChE/GSK-3 inhibition both in
terms of potency and equilibrium (AChE: IC50 = 51.1 nM;
GSK-3β: IC50 = 89.3 nM) and displayed significant
amelioration on cognitive deficits in scopolamine-induced amnesia
mice and efficient reduction against phosphorylation of tau protein
on Ser-199 and Ser-396 sites in glyceraldehyde (GA)-stimulated differentiated
SH-SY5Y cells. Furthermore, compound 27g exhibited eligible
pharmacokinetic properties, good kinase selectivity, and moderate
neuroprotection against GA-induced reduction in cell viability and
neurite damage in SH-SY5Y-derived neurons. The multifunctional profiles
of compound 27g suggest that it deserves further investigation
as a promising lead for the prospective treatment of AD.