Identification of dual-target isoxazolidine-isatin hybrids with antidiabetic potential: Design, synthesis, in vitro and multiscale molecular modeling approaches

In the development of novel antidiabetic agents, a novel series of isoxazolidine-isatin hybrids were designed, synthesized, and evaluated as dual α-amylase and α-glucosidase inhibitors. The precise structures of the synthesized scaffolds were characterized using different spectroscopic techniques and elemental analysis. The obtained results were compared to those of the reference drug, acarbose (IC₅₀ = 296.6 ± 0.825 μM for α-amylase & IC₅₀ = 780.4 ± 0.346 μM for α-glucosidase). Among the title compounds, 5d exhibited impressive α-amylase and α-glucosidase inhibitory activity with IC₅₀ values of 30.39 ± 1.52 μM and 65.1 ± 3.11 μM, respectively, followed by 5h (IC₅₀ = 46.65 ± 2.3 μM; IC₅₀ = 85.16 ± 4.25 μM) and 5f (IC₅₀ = 55.71 ± 2.78 μM; IC₅₀ = 106.77 ± 5.31 μM). Mechanistic studies revealed that the most potent derivative 5d bearing the chloro substituent attached to the oxoindolin-3-ylidene core, and acarbose, are a competitive inhibitors of α-amylase and α-glucosidase, respectively. Structure activity relationship (SAR) was examined to guide further structural optimization of the most appropriate substituent(s). Moreover, drug-likeness qualities and ADMET prediction of the most active analogue, 5d was also performed. Subsequently, 5d was subjected to molecular docking and dynamic simulation during the progression of 120 ns analysis to check the essential ligand-receptor patterns, and to estimate its stability. In silico studies were found in good agreement with the in vitro enzymatic inhibitions results. In conclusion, we demonstrated that most potent compound 5d could be exploited as dual potential inhibitor of α-amylase and α-glucosidase for possible management of diabetes.

Antidiabetic agents; Diabetes; Drug-likeness; Isoxazolidine-isatin hybrids; Kinetic study; Molecular docking and dynamics simulation.