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

ABSTRACT

To target the multi-facets of Alzheimer's disease (AD), a series of novel GSK-3ß inhibitors containing the 2,3-diaminopyridine moiety were designed and synthesized. The amide derivatives 5a-f showed moderate potency against GSK-3ß with weak Cu2+, Zn2+ and Al3+ chelating ability. The imine derivatives 9a, 9b and 9e were potent GSK-3ß inhibitors and selective Cu2+and Al3+ chelators. The 1,2-diamine derivatives 10a-e were strong metal-chelators, but decreased or lost their GSK-3ß inhibitory potency. In vitro, compounds 9a, 9b and 9e, especially 9b, exhibited good Cu2+-induced Aß aggregation inhibition, Cu2+-Aß 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+-Aß1-42 and H2O2-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-3ß inhibitors targeting multi-facets of AD.