Synthesis, DFT Studies, and Molecular Docking Evaluation of a Nortopsentin-Inspired Bis-Indole Furazan Derivative Targeting GSK-3Β

Abstract

Glycogen synthase kinase-3β (GSK-3β) is a key enzyme involved in various biochemical pathways and is a significant therapeutic target for neurodegenerative and metabolic diseases. In this study, a novel 3,4-bis(2-methyl-1H-indol-3-yl)-1,2,5-oxadiazole derivative (4c), inspired by the nortopsentin class of marine alkaloids, was designed and synthesized. The target bis-indole furazan derivative (4c) was efficiently synthesized via microwave-assisted cyclization of its bis-indole dioxime precursor (3a) in aqueous NaOH, providing a clean and catalyst-free strategy aligned with green chemistry principles. Structural characterization was achieved by FT-IR, ¹H-NMR, ¹³C-NMR, and elemental analysis and further validated through theoretical spectral calculations. Density functional theory (DFT) calculations provided insights into the molecular geometry, vibrational frequencies, and frontier molecular orbital characteristics of 4c. Molecular docking simulations against GSK-3β (PDB ID: 1Q41) revealed a favorable binding energy (-8.38 kcal/mol) and predicted inhibition constant of 0.725 µM. Computational ADME profiling also revealed acceptable drug-likeness properties. While the present findings are based solely on computational analyses, they indicate that bis-indole furazan derivatives could be considered as potential candidates for future optimization and experimental studies targeting GSK-3β.

Keywords

• Bis-indole
• Furazan
• Nortopsentin
• Computational chemistry
• GSK-3β

Ethical Statement

Ethics committee approval was not required for this study because of there was no study on animals or humans.

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