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

Purpose: To synthesize quinoxaline derivatives and investigate their inhibitory effects on glycogen synthase kinase (GSK)-3 beta 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-3 beta 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-3 beta, 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 mu M). 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-3 beta. 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-3 beta and is thus a promising scaffold for the development of novel drugs that can effectively inhibit GSK-3 beta signaling pathway.