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

alpha-Glucosidase inhibitors seem to be most effective in the treatment of diabetes. beta-Lactams have been reported to have some antidiabetic properties with alpha-glucosidase inhibitory activity. The current study aims to evaluate the potential of newly synthesized beta-lactams B8-B14 as alpha-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 beta-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, beta-lactams B8 and B9 proved to be potent inhibitors of alpha-glucosidase enzyme with IC50 values 3.33 mu M and 2.21 mu M, respectively, higher than the standard drug acarbose (IC50 = 5.47 mu M). 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 alpha-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 alpha-glucosidase enzyme with a binding affinity of -9.1 kcal mol-1, supporting its potential as a strong alpha-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 alpha-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 alpha-glucosidase inhibitory activity.