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

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