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

Lubna Swellmeen,Yusuf Al-Hiari,Rand Shaheen,Amal Uzrail

doi:10.4314/tjpr.v20i3.23

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.   

Highlights

Glycogen synthase kinase 3 (GSK-3), a highly ubiquitous serine/threonine kinase, has two isoforms: GSK-3α and GSK-3β [1]
Novel quinoxaline derivatives with quinolone nucleus were successfully synthesized via simple chemical reactions
The need to find novel GSK-3β inhibitors is of great importance, since the enzyme is involved in many biological processes

Summary

Introduction

Glycogen synthase kinase 3 (GSK-3), a highly ubiquitous serine/threonine kinase, has two isoforms: GSK-3α and GSK-3β [1]. Glycogen synthase is a key enzyme in biological processes such as apoptosis, intracellular communication, regulation of glucose metabolism and gene transcription [2]. The pathogeneses of type-2 diabetes mellitus (T2DM), Alzheimer’s disease (AD) and some cancers are thought to involve GSK-3β signaling pathway [3,4,5,6]. Overexpression of GSK-3β has been implicated in pancreatic, breast, and skin cancers [7,8]. Molecular modelling is used to unravel binding interactions between newly synthesized compounds and potential target enzymes/proteins [9,10]. The technique has been successfully employed for the elucidation of the crystal lattice structure of GSK-3β

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Results

Conclusion