Network Pharmacology-Driven Discovery of Isoxazole-Based Coumarin Derivatives as Potential α-Amylase Inhibitors: An Integrated In-Silico Study

AbstractDiabetes mellitus is a major metabolic disorder characterized by chronic hyperglycemia, necessitatingthe development of safer and more effective therapeutic agents. Inhibition of α-amylase is anestablished strategy for reducing postprandial blood glucose levels by delaying carbohydratedigestion. In the present study, a series of novel isoxazole-based coumarin derivatives were designed,synthesized, and evaluated as potential α-amylase inhibitors using an integrated computational andbiological framework. First, network pharmacology analysis was conducted to construct compound-target-disease interaction networks, elucidating the multi-target mechanisms, biological pathways, andkey signaling nodes involved in glycemic control. To assess the therapeutic viability of these activecandidates, in silico ADMET profiling was subsequently performed, confirming that the majority ofthe derivatives exhibited acceptable drug-likeness, pharmacokinetic parameters, and low predictedtoxicity profiles. Molecular docking studies were then executed to evaluate the binding affinity andspecific interaction patterns of the prioritized compounds within the active site of α-amylase,demonstrating strong binding and favorable hydrogen bonding with key catalytic residues. Followingthe computational pipeline, the target compounds were synthesized and structurally characterizedusing standard analytical techniques. In vitro α-amylase inhibitory assays were conducted usingacarbose as the reference standard, confirming that several synthesized derivatives possessedpromising enzyme inhibitory activity. Overall, the combined systems-level, pharmacokinetic, andbiological findings highlight isoxazole-based coumarin scaffolds as attractive candidates for thedevelopment of novel antidiabetic therapeutics.