Development of Bisindole-Substituted Aminopyrazoles as Novel GSK-3β Inhibitors with Suppressive Effects against Microglial Inflammation and Oxidative Neurotoxicity.
Jian-Guo LiuDanfeng ZhaoQi GongFengxia BaoWen-Wen ChenHai Yan ZhangMing-Hua XuPublished in: ACS chemical neuroscience (2020)
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.
Keyphrases
- lps induced
- signaling pathway
- inflammatory response
- pi k akt
- induced apoptosis
- cell cycle arrest
- anti inflammatory
- lipopolysaccharide induced
- oxidative stress
- molecular docking
- small molecule
- cell proliferation
- toll like receptor
- multiple sclerosis
- high glucose
- protein kinase
- diabetic rats
- cell death
- high throughput
- metabolic syndrome
- white matter
- endothelial cells
- tyrosine kinase
- single cell
- subarachnoid hemorrhage
- high intensity
- high fat diet induced
- insulin resistance
- case control
- resting state
- functional connectivity
- stress induced