Exploring the Antidiabetic Potential of Newly Synthesized α-Aminophosphonate–Coumarin Hybrids: Design, Synthesis, In Silico Docking, and Biological Evaluation

Objective: One of the most prevalent diseases that significantly raise the global burden of disease is diabetes mellitus, which is linked to a number of secondary metabolic disorders. In this work, we designed and synthesized a novel series of α-aminophosphonate–coumarin hybrids as potential antidiabetic agents. Methods: The compounds were efficiently synthesized via a multicomponent Kabachnik–Fields reaction. Their structures were verified by spectral analysis (IR, NMR, MS), melting point determination, and TLC. An in silico docking study evaluating their binding capacity to the insulin receptor was performed using AutoDock Tools 1.5.4 to prepare the input files. Results and Discussion: Molecular docking suggested that compounds 4f, 4b, 4c, and 4e could act as potential antidiabetic templates. In vivo evaluation was conducted on a rat model of type II diabetes induced by streptozotocin (STZ) and nicotinamide (NA). Treatment with compounds 4f and 4b (30 mg/kg body weight) significantly and moderately suppressed fasting blood glucose levels, respectively, compared to diabetic controls. Furthermore, treatment with 4f and 4b dose-dependently reduced oxidative stress markers, including lipid peroxidation (MDA) and superoxide dismutase (SOD) activity, while increasing glutathione (GSH) levels in the pancreas and liver. Histological examination revealed that the architecture of liver and pancreatic tissues was less affected by 4f treatment compared to the diabetic control. Conclusions: The findings indicate that the synthesized coumarin–based α-aminophosphonates, particularly compound 4f, exhibit promising antioxidant and antihyperglycemic effects in a rat model of STZ-NA-mediated type II diabetes.