Bis-Schiff bases as potent antidiabetic agents: Synthesis, enzyme inhibition, molecular docking and dynamic simulations

Bis-Schiff bases are significant compounds in medicinal chemistry due to the inhibition of α-amylase and α-glucosidase enzymes. A series of bis-Schiff bases of 4-hydroxyacetophenone were synthesized, characterized and tested for their in vitro α-amylase and α-glucosidase inhibitory activities. Among the series, seven compounds (2d, 2c, 2q, 2i, 2h, 2a, and 2g) attributed excellent inhibitory effect with IC₅₀ values ranging from (IC₅₀ = 3.95 ± 0.09 for α-amylase and 4.33 ± 0.07 µM for α-glucosidase) to (IC₅₀ = 19.64 ± 0.04 for α-amylase and 21.53 ± 0.05 µM for α-glucosidase). Similarly, five compounds were found moderate active while the remaining five compounds showed less inhibitory activities by comparing with the standard acarbose. The structure activity relationship (SAR) study showed that the existence of electron donating groups (methoxy and hydroxyl) increases the inhibitory activities of the compounds. The molecular docking study against α-amylase, revealed a reasonable correlation between docking scores and IC₅₀ values was observed for the synthesized series, validating the docking approach for ranking these analogues. This work highpoints the synthetic bis-Schiff bases as hopeful antidiabetic agents based on their potent α-amylase and α-glucosidase inhibition.