Structure-activity relationship of novel Copper(II) complexes as dual inhibitors of α-amylase and α-glucosidase: insights from X-ray crystallography and molecular docking.

This study investigated the relationship between the structures of new Copper(II) complexes and their potential hypoglycemic activities, and verified this relationship through molecular docking. Five new Cu(II) metal complexes were formed using three benzotriazole ligands, and their potential hypoglycemic activities were evaluated. The X-ray single crystal diffraction results indicate that complexes 1, 4, and 5 have a one-dimensional chain structure, while complex 2 has a mononuclear structure and complex 3 has a binuclear structure. Complexes 1-5 all exhibited better inhibitory activity against α-amylase than the positive control acarbose (IC50 value was 4.45 ± 0.06 mmol/L). Among them, complexes 1, 3, 4, and 5 had better inhibitory activity against α-amylase, with their IC50 values being 1.60 ± 0.01 mmol/L, 1.55 ± 0.06 mmol/L, 2.52 ± 0.07 mmol/L, and 3.02 ± 0.03 mmol/L, respectively. The results of the α-glucosidase inhibition experiment showed that the IC50 values of complexes 1, 3, and 5 for α-glucosidase were 2.45 ± 0.06 μmol/L, 2.39 ± 0.03 μmol/L, and 3.26 ± 0.10 μmol/L, respectively. At a concentration of 7 μM, the inhibition rates all exceeded 90%. Meanwhile, molecular docking results showed that complexes 1, 3, and 5 had relatively strong binding affinities for α-glucosidase, which is consistent with the results of the enzyme inhibition assays. In addition, complexes 1, 3, and 5 significantly improved the glucose consumption of IR-HepG2 cells, with values 1.88, 1.90, and 1.81 times that of the model group, respectively. This work is based on the precise single-crystal structure of the complexes. It systematically determined the enzyme inhibitory activity, conducted molecular docking simulations, and at the molecular level, revealed and clarified the structure-activity relationship between the complexes and the enzyme active pocket. This provided an intuitive and reliable structural basis for understanding the inhibition mechanism. The results show that complexes have better inhibitory activities against α-amylase and α-glucosidase than the corresponding ligands and metal salts. This indicates that the cooperative effect between Cu(II) and the ligands enhances the potential hypoglycemic activity of the complexes. The enzyme inhibitory activity of the complexes is closely related to the coordination mode and spatial steric hindrance of the metal center.