Synthesis and evaluation of novel GSK-3β inhibitors as multifunctional agents against Alzheimer's disease.

To target the multi-facets of Alzheimer's disease (AD), a series of novel GSK-3β inhibitors containing the 2,3-diaminopyridine moiety were designed and synthesized. The amide derivatives 5a-f showed moderate potency against GSK-3β with weak Cu2+ , Zn2+ and Al3+ chelating ability. The imine derivatives 9a, 9b and 9e were potent GSK-3β inhibitors and selective Cu2+ and Al3+ chelators. The 1,2-diamine derivatives 10a-e were strong metal-chelators, but decreased or lost their GSK-3β inhibitory potency. In vitro, compounds 9a, 9b and 9e, especially 9b, exhibited good Cu2+ -induced Aβ aggregation inhibition, Cu2+ -Aβ complex disaggregation, ROS formation inhibition, and antioxidant activities. In cells, compounds 9a, 9b and 9e can inhibit tau protein phosphorylation and protect neuro cells against Cu2+ -Aβ1-42 and H2 O2 -induced cell damage. Furthermore, compound 9b was predicted to have the ability to pass the BBB with drug likeness properties. Therefore, compound 9b might be a good lead for the development of novel GSK-3β inhibitors targeting multi-facets of AD.