Synthesis of benzimidazole based thiadiazole and carbohydrazide conjugates as glycogen synthase kinase-3β inhibitors with anti-depressant activity

Bioorg Med Chem Lett. 2016 Aug 15;26(16):4020-4. doi: 10.1016/j.bmcl.2016.06.084. Epub 2016 Jun 30.

Abstract

A series of benzimidazole based thiadiazole and carbohydrazide conjugates have been synthesized and evaluated for inhibition of glycogen synthase kinase-3β and anti-depressant effect. Compounds 4f, 4j, 5b, 5g and 5i were found to be the most potent inhibitors of GSK-3β in vitro amongst the twenty-five benzimidazole based thiadiazole and carbohydrazide conjugates synthesized. Compound 5i was also found to exhibit significant antidepressant activity in vivo at 50mg/kg, when compared to fluoxetine, a known antidepressant drug. The molecular docking studies revealed multiple hydrogen bond interactions by the synthesized compounds with various amino acid residues, viz, ASP-133, LYS-183, PRO-136, VAL-135, TYR-134, or LYS-60 at the GSK-3β receptor site.

Keywords: Benzimidazole; Carbohydrazide; Glycogen synthase kinase; Molecular docking; Thiadiazole.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antipsychotic Agents / chemical synthesis*
  • Antipsychotic Agents / chemistry
  • Antipsychotic Agents / pharmacology
  • Behavior, Animal / drug effects
  • Benzimidazoles / chemical synthesis
  • Benzimidazoles / chemistry*
  • Benzimidazoles / pharmacology
  • Binding Sites
  • Glycogen Synthase Kinase 3 beta / antagonists & inhibitors*
  • Glycogen Synthase Kinase 3 beta / metabolism
  • Hydrazines / chemistry
  • Hydrogen Bonding
  • Maze Learning / drug effects
  • Mice
  • Molecular Docking Simulation
  • Protein Structure, Tertiary
  • Thiadiazoles / chemistry

Substances

  • Antipsychotic Agents
  • Benzimidazoles
  • Hydrazines
  • Thiadiazoles
  • benzimidazole
  • Glycogen Synthase Kinase 3 beta
  • carbohydrazide