Synthesis, docking, and biological evaluation of novel 1-benzyl-4-(4-(R)-5-sulfonylidene-4,5-dihydro-1H-1,2,4-triazol-3-yl)pyrrolidin-2-ones as potential nootropic agents

Eur J Med Chem. 2022 Dec 15;244:114823. doi: 10.1016/j.ejmech.2022.114823. Epub 2022 Oct 7.


In order to search for innovative nootropic agents, new 1-benzyl-4- (4- (R)-5-sulfonylidene-4,5-dihydro-1H-1,2,4-triazol-3-yl) pyrrolidine-2-ones was synthesized by reacting benzylamine with itaconic acid to 1-benzyl-5-oxopyrrolidine-3-carboxylic acid, which was then subjected to hydrazinolysis followed by the addition of substituted isothiacyanate followed by cyclization of intermediate thiosemicarbazides. The structure and purity of the obtained substances were confirmed by elemental analysis, 1H NMR spectroscopy, 13C NMR spectroscopy and LC/MS. Docking studies were performed for the substances synthesized using Autodock 4.2 software. Approximate values of LD50 (in silico determination) are around 870-1000 mg/kg. All synthesized substances were tested for nootropic activity by the passive avoidance test on the scopolamine amnesia model in doses that are about 1/10 of the estimated LD50. Based on the results of docking and pharmacological experiment, the most promising substances 7a, as well as 7e, 7f were identified. The results of molecular docking (hit compound 7a) indicate a positive correlation between the obtained values of docking studies and experimental data.

Keywords: 1-Benzyl-4-(4-(R)-5-Sulfonylidene-4,5-dihydro-1H-1,2,4-triazol-3-yl)pyrrolidin-2-ones; Docking studies; Nootropic activity; Synthesis.

MeSH terms

  • Chromatography, Liquid
  • Magnetic Resonance Spectroscopy
  • Mass Spectrometry / methods
  • Molecular Docking Simulation
  • Nootropic Agents* / chemical synthesis
  • Nootropic Agents* / chemistry
  • Nootropic Agents* / pharmacology
  • Pyrrolidinones* / chemical synthesis
  • Pyrrolidinones* / chemistry
  • Pyrrolidinones* / pharmacology
  • Structure-Activity Relationship


  • Nootropic Agents
  • Pyrrolidinones