Tropical Journal of Pharmaceutical Research

Original Research Article | OPEN ACCESS

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

Lubna Swellmeen¹ , Amal Uzrail², Rand Shaheen³, Yusuf AL Hiari⁴

¹Department of Pharmaceutical Sciences, Faculty of Pharmacy, Zarqa University; ²Department of Medical Analysis, Faculty of Sciences, Al-Albayt University; ³Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Hashemite University; ⁴Faculty of Pharmacy, The University of Jordan, Amman, Jordan.

For correspondence:- Lubna Swellmeen Email: lswellmeen@zu.edu.jo Tel:+962778004500

Accepted: 16 February 2021 Published: 31 March 2021

Citation: Swellmeen L, Uzrail A, Shaheen R, Hiari YA. Molecular modelling studies and synthesis of novel quinoxaline derivatives with potential inhibitory effect on GSK-3β. Trop J Pharm Res 2021; 20(3):599-604 doi: 10.4314/tjpr.v20i3.23

© 2021 The authors.
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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.

Keywords: Quinoxaline derivatives, Glycogen synthase kinase (GSK)-3β, Molecular docking, Quinoline nucleus