Discovery of Azaindolin-2-One as a Dual Inhibitor of GSK3β and Tau Aggregation with Potential Neuroprotective Activity.

Abstract

The inhibition of glycogen synthase kinase 3β (GSK3β) activity through pharmacological intervention represents a promising approach for treating challenging neurodegenerative disorders like Alzheimer's disease. Similarly, abnormal tau aggregate accumulation in neurons is a hallmark of various neurodegenerative diseases. We introduced new dual GSK3β/tau aggregation inhibitors due to the excellent clinical outcome of multitarget drugs. Compound (E)-2f stands out among the synthesized inhibitors as a promising GSK3β inhibitor (IC50 1.7 µM) with a pronounced tau anti-aggregation effect in a cell-based model of tauopathy. Concurrently, (E)-2f was demonstrated to be non-toxic to normal cells, making it a promising neuroprotective lead compound that needs further investigation.

• Authors: Taha F S Ali, Halil I Ciftci, Mohamed O Radwan, Eslam Roshdy, Ahmed M Shawky, Mohammed A S Abourehab, Hiroshi Tateishi, Masami Otsuka, Mikako Fujita
• Journal: Pharmaceuticals (Basel, Switzerland) (Pharmaceuticals (Basel)) Vol. 15 Issue 4 (Mar 31 2022) ISSN: 1424-8247 [Print] Switzerland
• PMID: 35455423 (Publication Type: Journal Article)