Molecular modelling studies and synthesis of novel quinoxaline derivatives with potential inhibitory effect on GSK-3β

  • Lubna Swellmeen
  • Amal Uzrail
  • Rand Shaheen
  • Yusuf Al-Hiari
Keywords: Quinoxaline derivatives, Glycogen synthase kinase (GSK)-3β, Molecular docking, Quinoline nucleus

Abstract

Purpose: To synthesize quinoxaline derivatives and investigate their inhibitory effects on glycogen synthase kinase (GSK)-3β in vitro.

Methods: Quinoxaline derivatives were synthesized via reaction between synthon 1 and DL- 2-amino succinic acid, and subsequent lactamization reaction. The new compounds were tested against GSK-3β in vitro to select the most potent compound which was then used for molecular modelling.

Results: Novel quinoxaline derivatives with quinolone nucleus were successfully synthesized via simple chemical reactions. The compounds markedly inhibited GSK-3β, with compound 45 [3-(carboxymethyl)- 5-fluoro-10-(4-fluorophenyl)-2,7-dioxo-1,2,3,4,7,10-hexahydropyrido [2,3-f] quinoxaline-8-carboxylic acid] achieving the best effect (IC50 = 0.18 μM). The half maximal inhibitory concentrations (IC50) of the compounds were in micromolar range. Molecular modelling revealed several interactions between compound 45 and the binding site of GSK-3β.

Conclusion: These results indicate that 3-(carboxymethyl)-5-fluoro-10-(4-fluorophenyl)-2,7-dioxo- 1,2,3,4,7,10-hexahydropyrido [2,3-f] quinoxaline-8-carboxylic acid is a potent inhibitor of GSK-3β and is thus a promising scaffold for the development of novel drugs that can effectively inhibit GSK-3β signaling pathway.

Published
2022-01-17
Section
Articles

Journal Identifiers


eISSN: 1596-9827
print ISSN: 1596-5996