Coumarin-based small molecules for diabetes management: rational design, computational studies, synthesis, and...

Diabetes mellitus is a chronic metabolic disorder that requires the development of safer and more effective therapeutic agents. In the present study, a series of novel coumarin-oxazole hybrid derivatives were rationally designed, synthesized, and evaluated for their potential antidiabetic activity through inhibition of α-amylase and α-glucosidase enzymes. Molecular docking studies performed against human pancreatic α-amylase (PDB ID: 4GQR) demonstrated strong binding affinities for compounds SAK5, SAK8, SAK9, SAK10 and SAK13 with favourable interactions at key catalytic residues. In silico ADMET analysis indicated desirable pharmacokinetic properties, including good gastrointestinal absorption, optimal lipophilicity, acceptable blood-brain barrier permeability, and non-carcinogenic as well as non-mutagenic profiles. Structural characterization of the synthesized compounds was confirmed using FT-IR, NMR and MS spectroscopy methods, ensuring their identity and purity. In vitro enzyme inhibition assays demonstrated notable inhibitory activity against both α-amylase and α-glucosidase. Among the synthesized derivatives, SAK9 exhibited the highest activity, with IC₅₀ values of 111.60 μg/mL and 104.67 μg/mL against α-amylase and α-glucosidase, respectively, followed by SAK8 (117.23 and 109.86 μg/mL) and SAK10 (144.71 and 133.22 μg/mL). Although less potent than the reference drug acarbose (IC₅₀ = 92.85 and 65.59 μg/mL, respectively), these findings indicate that the synthesized coumarin-based derivatives possess promising antidiabetic potential. Furthermore, molecular dynamics simulations highlighted the stability of the most potent compound, SAK9, which maintained consistent protein-ligand interactions throughout 100 ns simulation period. Overall, the findings suggest that coumarin-oxazole hybrids represent promising lead candidates for the development of novel antidiabetic agents with enhanced efficacy and safety profiles.