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

Bioorg Med Chem Lett. 2023 May 1:87:129283. doi: 10.1016/j.bmcl.2023.129283. Epub 2023 Apr 11.

Abstract

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 GSK3β inhibitors in a series of 3-arylidene-2-oxindole derivatives. Considering the putative role of GSK3β in platelet activation, the most active compounds were evaluated for antiplatelet activity and antithrombotic activity. It was found that GSK3β 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 GSK3β 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 GSK3β inhibitors for development of novel antithrombotic agents.

Keywords: GSK3β; Oxindole; Platelet; Thrombosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • COVID-19*
  • Fibrinolytic Agents / pharmacology
  • Fibrinolytic Agents / therapeutic use
  • Glycogen Synthase Kinase 3 beta
  • Humans
  • Oxindoles / pharmacology
  • Platelet Aggregation
  • Platelet Aggregation Inhibitors / pharmacology
  • Platelet Aggregation Inhibitors / therapeutic use
  • Thrombosis* / drug therapy
  • Thrombosis* / prevention & control

Substances

  • Platelet Aggregation Inhibitors
  • 2-oxindole
  • Oxindoles
  • Fibrinolytic Agents
  • Glycogen Synthase Kinase 3 beta