Synthesis and Evaluation of 3-(furo[2,3 -b]pyridin-3-yl)-4-(1H-indol-3-yl)-maleimides as Novel GSK-3 β Inhibitors and Anti-Ischemic Agents.

A series of novel 3-(furo[2,3 -b]pyridin-3-yl)-4-(1H-indol-3-yl)-maleimides were designed, synthesized, and biologically evaluated for their GSK-3 β inhibitory activities. Most compounds showed favorable inhibitory activities against GSK-3 β protein. Among them, compounds 5n, 5o, and 5p significantly reduced GSK-3 β substrate tau phosphorylation at Ser396 in primary neurons, indicating inhibition of cellular GSK-3 β activity. In the in vitro neuronal injury models, compounds 5n, 5o, and 5p prevented neuronal death against glutamate, oxygen-glucose deprivation, and nutrient serum deprivation which are closely associated with cerebral ischemic stroke. In the in vivo cerebral ischemia animal model, compound 5o reduced infarct size by 10% and improved the neurological deficit. The results may provide new insights into the development of novel GSK-3 β inhibitors with potential neuroprotective activity against brain ischemic stroke. [ABSTRACT FROM AUTHOR]