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

摘要

To target the multi-facets of Alzheimer's disease (AD), a series of novel GSK-3P inhibitors containing the 2,3-diaminopyridine moiety were designed and synthesized. The amide derivatives 5a-f showed moderate potency against GSK-3 beta with weak Cu2+, Zn2+ and Al3+ chelating ability. The imine derivatives 9a, 9b and 9e were potent GSK-3 beta inhibitors and selective Cu2+ and Al3+ chelators. The 1,2-diamine derivatives 10a-e were strong metal-chelators, but decreased or lost their GSK-3 beta inhibitory potency. In vitro, compounds 9a, 9b and 9e, especially 9b, exhibited good Cu2+-induced AP aggregation inhibition, Cu2+-A beta 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+-A beta(1) -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-3 beta inhibitors targeting multi-facets of AD. (C) 2019 Elsevier Masson SAS. All rights reserved.