Development of Bisindole-Substituted Aminopyrazoles as Novel GSK-3β Inhibitors with Suppressive Effects against Microglial Inflammation and Oxidative Neurotoxicity.

Abstract

Development of glycogen synthase kinase-3β (GSK-3β) inactivation-centric agents with polypharmacological profiles is increasingly recognized as a promising therapeutic strategy against the multifactorial etiopathology of Alzheimer's disease (AD). In this respect, a series of disubstituted aminopyrazole derivatives were designed and synthesized as a new class of GSK-3β inhibitors. Most of these derivatives possess GSK-3β inhibitory activities with IC50 values in the micromolar ranges, among which bisindole-substituted aminopyrazole derivative 6h displayed moderate GSK-3β inhibition (IC50 = 1.76 ± 0.19 μM), and alleviative effects against lipopolysaccharide (LPS)-induced glial inflammation in BV-2 cells and glutamate-induced oxidative neurotoxicity in HT-22 cells. Further in vivo studies indicated that compound 6h had potent anti-inflammatory effect, by showing markedly reduced microglial activation and astrocyte proliferation in the brain of LPS-injected mice. Overall, the simultaneous modulation of 6h on multiple dysfunctions of disease network highlights this structural distinctively bisindole-substituted aminopyrazole could be a useful prototype for the discovery of novel therapeutic agents to tackle AD and other GSK-3β associated complex neurological syndromes.