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

Abstract

Aims: To synthesise and evaluate new amino biaryl-urea (3a-h) and Schiff base urea derivatives (5a-h) for their in vitro antidiabetic activity against α-glucosidase and α-amylase.

Materials and methods: 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 (3a-h), 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.

Results: Derivatives 3g and 3h 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 3g interacts with key residues TRP59 and GLN63 of α-amylase, supporting the experimental findings.

Conclusions: The di-fluoro and di-chloro substituents in compounds 3g and 3 h 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.

Keywords: Schiff base; Synthesis; molecular docking; molecular dynamics; α-amylase; α-glucosidase.