3-Arylidene-2-oxindoles as GSK3β inhibitors and anti-thrombotic agents

Development of novel agents that prevent thrombotic events is an urgent task considering increasing incidence of cardiovascular diseases and coagulopathies that accompany cancer and COVID-19. Enzymatic assay identified novel GSK3 beta inhibitors in a series of 3-arylidene-2-oxindole derivatives. Considering the putative role of GSK3 beta in platelet activation, the most active compounds were evaluated for antiplatelet activity and antithrombotic activity. It was found that GSK3 beta inhibition by 2-oxindoles correlates with inhibition of platelet activation only for compounds 1b and 5a. Albeit, in vitro antiplatelet activity matched well with in vivo anti-thrombosis activity. The most active GSK3 beta inhibitor 5a exceeds antiplatelet activity of acetylsalicylic acid in vitro by 10.3 times and antithrombotic activity in vivo by 18.7 times (ED50 7.3 mg/kg). These results support the promising role of GSK3 beta inhibitors for development of novel antithrombotic agents.

Automated summary

Development of novel agents that prevent thrombotic events is urgently needed, and GSK3 beta inhibitors showed promising results. The most active compound, 5a, demonstrated significantly higher antiplatelet and antithrombotic activities compared to acetylsalicylic acid. These findings support the potential role of GSK3 beta inhibitors in the development of new antithrombotic agents.