Design, synthesis, and computational assessment of bis‑oxadiazole ligands targeting α-amylase and α-glucosidase: DFT, docking, and ADME studies.
TL;DR
The combined experimental and computational results demonstrate significant structure-activity relationships within the bis-oxadiazole scaffold, identifying compound 10 as a promising lead candidate for further optimization as a dual enzyme inhibitor for diabetes management.
Abstract
Aim
Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by persistent hyperglycemia, mainly due to postprandial glucose elevation. Inhibition of carbohydrate-hydrolyzing enzymes such as α-glucosidase and α-amylase is an effective strategy for its management. This study aimed to design, synthesize, characterize, and evaluate a series of bis-oxadiazole derivatives as potential anti-diabetic agents.
Methods
The target compounds were synthesized via multistep organic synthesis and structurally confirmed using spectroscopic techniques including FTIR, NMR, and HRMS. The in-vitro anti-diabetic potential was assessed through α-glucosidase and α-amylase inhibition assays. In addition, molecular docking studies were performed to investigate binding interactions and conformational stability within the active sites of both enzymes. Absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiling was also carried out to evaluate drug-likeness and pharmacokinetic properties.
Results
Among the synthesized derivatives, compound 10 exhibited the most potent activity, showing IC50 values of 1.80 and 2.10 μM against α-amylase and α-glucosidase, respectively, in comparison with the positive control acarbose (IC50 = 5.50 and 5.60 μM, respectively). Compound 10 exhibited the most potent inhibitory activity against both enzymes, showing strong binding affinity and key hydrogen-bonding and hydrophobic interactions in docking studies. The spectroscopic characterization confirmed the successful formation of all target compounds. ADMET analysis indicated favorable pharmacokinetic and toxicity profiles for the most active derivatives.
Conclusion
The combined experimental and computational results demonstrate significant structure-activity relationships within the bis-oxadiazole scaffold, identifying compound 10 as a promising lead candidate for further optimization as a dual enzyme inhibitor for diabetes management.