Discovery of 4-aminochalcone-based dual α-glucosidase and aldose reductase inhibitors: in vitro, in vivo, and in silico studies.

Diabetes mellitus is a chronic metabolic disorder associated with persistent hyperglycemia and the development of numerous secondary complications. In the present study, a series of 4-aminochalcone derivatives (1N-10N) were synthesized and evaluated as potential dual inhibitors of α-glucosidase and aldose reductase using integrated in vitro, in vivo, and in silico approaches. The synthesized compounds were screened for their inhibitory activities against both target enzymes. Several derivatives exhibited remarkable inhibitory activity, displaying nanomolar IC50 values against α-glucosidase and micromolar IC50 values against aldose reductase, demonstrating the suitability of the 4-aminochalcone scaffold for dual-target antidiabetic drug development. The antidiabetic potential of the most active compounds was further investigated in streptozotocin-induced diabetic rats. To the best of our knowledge, this represents the first report describing the evaluation of 4-aminochalcone derivatives as aldose reductase inhibitors and their subsequent in vivo antidiabetic assessment in streptozotocin-induced diabetic rats. Treatment with the selected derivatives improved glycemic control and favorably modulated diabetes-associated physiological and biochemical alterations, including body weight changes, lipid profile disturbances, and elevated hepatic biomarkers. Molecular docking studies were performed to investigate the binding modes of the synthesized compounds within the active sites of α-glucosidase and aldose reductase, while molecular dynamics simulations were conducted to assess the stability of the protein-ligand complexes over time. Furthermore, density functional theory (DFT) calculations were employed to explore the electronic properties and reactivity patterns of the synthesized derivatives. In addition, ADMET analysis was performed to assess their pharmacokinetic and drug-likeness characteristics. These findings support 4-aminochalcones as promising dual α-glucosidase and aldose reductase inhibitors.