Synthesis and biological evaluation of β-lactams as potent antidiabetic agents†

α-Glucosidase inhibitors seem to be most effective in the treatment of diabetes. β-Lactams have been reported to have some antidiabetic properties with α-glucosidase inhibitory activity. The current study aims to evaluate the potential of newly synthesized β-lactams B8–B14 as α-glucosidase inhibitors that can help to control high blood glucose levels in type 2 diabetes mellitus. The synthesized 3-nitrophenyl imine derivatives (1 eq.) reacted with ethenone (1 eq.) in benzene by a Staudinger cycloaddition reaction to afford β-lactams B8–B14, which was confirmed by advanced spectroscopic techniques and elemental analysis. The antihyperglycemic studies revealed that compounds B8, B9 and B12–B14 at a dosage of 5 mg kg⁻¹ and after 24 h of administration showed a higher percentage decrease in blood sugar (12.61–21.07%) than the reference drug glibenclamide (11.74%). In line with in vitro studies, β-lactams B8 and B9 proved to be potent inhibitors of α-glucosidase enzyme with IC₅₀ values 3.33 μM and 2.21 μM, respectively, higher than the standard drug acarbose (IC₅₀ = 5.47 μM). Further, in vivo experiments confirmed that the most potent antidiabetic agents B8 and B9 significantly decrease the ALT level (71.1–74.3%) to prevent liver injury induced by diabetes. The higher antioxidant potential confirmed the role of B9 as a lead antidiabetic agent to manage the ROS generated by diabetes. AutoDock Vina was used to identify the catalytic sites of α-glucosidase and to remove water molecules and add hydrogen and Kollman charges to the protein structure. In molecular docking studies, B9 fits tightly within the catalytic pocket of the α-glucosidase enzyme with a binding affinity of −9.1 kcal mol⁻¹, supporting its potential as a strong α-glucosidase inhibitor. The most potent compound, B9, was found to have optimal lipophilicity (2.63), the highest drug-likeness (86.9%) and excellent gastrointestinal absorption that are suitable for bioavailability and drug design. Moreover, these physiochemical properties also showed excellent correlation with the α-glucosidase inhibitory and antidiabetic activity. Overall, these excellent results suggest that the most potent compound, B9, has the potential to develop as a therapeutic drug in the future to treat diabetes with α-glucosidase inhibitory activity.