Synthesis And Biological Evaluation Of Novel 4,5-Bisindolyl-1,2,4-Triazol-3-Ones As Glycogen Synthase Kinase-3 Beta Inhibitors And Neuroprotective Agents

A series of novel 4,5-bisindolyl-1,2,4-triazol-3-ones were designed, prepared and evaluated for their glycogen synthase kinase (GSK)-3 beta inhibitory activities. Compounds exhibited favorable inhibitory potency towards GSK-3 beta kinase at the molecular level and in cells indicated by significantly reducing GSK-3 beta substrate Tau phosphorylation at Ser396 in primary neurons showing the inhibition of cellular GSK-3 beta. In an in vitro model of neuronal injury, compounds 6b, 6d and 6f prevented glutamate-induced neuronal death which was closely associated with cerebral ischemic stroke. Preliminary structure-activity relationship was examined and showed that different substituents on the indole ring had significant influences on the GSK-3 beta inhibitory potency. These findings may provide new insights into the development of novel GSK-3 beta inhibitors as neuroprotective agents.