Synthesis and docking of new Schiff-bases bearing urea as promising dual α-amylase and α-glucosidase inhibitors

To synthesise and evaluate new amino biaryl-urea (<b>3a-h)</b> and Schiff base urea derivatives (<b>5a-h</b>) for their in vitro antidiabetic activity against α-glucosidase and α-amylase. A series of Schiff base urea derivatives were synthesised through a two-step procedure: condensation of 4-chloro-o-phenylenediamine with isocyanates to form amino biaryl-urea derivatives (<b>3a-h</b>), followed by reaction with 2-hydroxy-naphthaldehyde. The new compounds were characterized using ¹H and ¹³C NMR, as well as high-resolution mass spectrometry. Inhibition assays were conducted to determine IC₅₀ values of all compounds against α-amylase and α-glucosidase. Derivatives <b>3g</b> and <b>3h</b> exhibited the strongest enzyme inhibition, with IC₅₀ values of 10.06 ± 0.32 µM (α-amylase) and 21.23 ± 1.27 µM (α-glucosidase), respectively. These compounds displayed activity comparable to the standard drug acarbose. Docking studies revealed that <b>3g</b> interacts with key residues TRP59 and GLN63 of α-amylase, supporting the experimental findings. The di-fluoro and di-chloro substituents in compounds <b>3g</b> and <b>3 h</b> enhance their antidiabetic activity, suggesting their potential as effective inhibitors of carbohydrate-metabolizing enzymes. Further studies are warranted to explore the therapeutic applications of these derivatives.