Synthesis, biological activities, and evaluation molecular docking-dynamics studies of new phenylisoxazole quinoxalin-2-amine hybrids as potential α-amylase and α-glucosidase inhibitors

Siti Nurshahira Mohd Radzuan, Lacksany Phongphane, Mohamad Hafizi Abu Bakar, Mohammad Tasyriq Che Omar, Nor Shafiqah Nor Shahril, Unang Supratman, Desi Harneti, Habibah A. Wahabe, Mohamad Nurul Azmi
https://doi.org/10.1039/D3RA08642A

Abstract

New phenylisoxazole quinoxalin-2-amine hybrids 5a–i were successfully synthesised with yields of 53–85% and characterised with various spectroscopy methods. The synthesised hybrids underwent in vitro α-amylase and α-glucosidase inhibitory assays, with acarbose as the positive control. Through the biological study, compound 5h exhibits the highest α-amylase inhibitory activity with IC₅₀ = 16.4 ± 0.1 μM while compounds 5a–c, 5e and 5h exhibit great potential as α-glucosidase inhibitors, with 5c being the most potent (IC₅₀ = 15.2 ± 0.3 μM). Among the compounds, 5h exhibits potential as a dual inhibitor for both α-amylase (IC₅₀ = 16.4 ± 0.1 μM) and α-glucosidase (IC₅₀ = 31.6 ± 0.4 μM) enzymes. Through the molecular docking studies, the inhibition potential of the selected compounds is supported. Compound 5h showed important interactions with α-amylase enzyme active sites and exhibited the highest binding energy of −8.9 ± 0.10 kcal mol⁻¹, while compound 5c exhibited the highest binding energy of −9.0 ± 0.20 kcal mol⁻¹ by forming important interactions with the α-glucosidase enzyme active sites. The molecular dynamics study showed that the selected compounds exhibited relative stability when binding with α-amylase and α-glucosidase enzymes. Additionally, compound 5h demonstrated a similar pattern of motion and mechanism of action as the commercially available miglitol.

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