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

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.
 
 
 

Targeting GSK-3β enzyme by diazepino-quinolone derivatives

“…The synthetic procedure used in scheme I is based on reported methods [10,15]. By applying three steps of reaction, synthon I was obtained: The first step was done by reacting synthon a, and b with different 3-aminopropanoic acid derivatives under conditions shown in Figure 2, and the reaction was done under reflux at 80 o C then solution of sodium dithionite (8.0 g, 46 mmol) was added.…”

“…The GSK-3β enzyme inhibitors have gained a lot of interest as a potential treatment of neurodegenerative diseases such as Alzheimer´s disease [7], diabetes [2] and malignancies [8,9]. The enzyme inhibitors were previously synthesized from heterocyclic compounds having a quinoxaline nucleus that showed good inhibitory activity against GSK-3β enzyme [10].…”