Exploring the synthesis, molecular structure and biological activities of novel Bis-Schiff base derivatives: A combined theoretical and experimental approach

•Synthesis of six novel bis-Schiff base derivatives (2a-f) based on 2,4-dihydroxy acetophenone moiety, their structures were confirmed through modern spectroscopic techniques (HR-ESI-MS, 1H, & 13CNMR ) and finally evaluated for their in vitro α-glucosidase and α-amylase inhibitory activities.•All these compounds exhibited excellent to good inhibitory activities when compared with the standard acarbose.•DFT study was utilized to explore the FMO, indicating bioactivity, stability, and charge transfer of the synthesized product compounds. Similarly, MEP analysis showed electrostatic potential distribution on molecular surfaces for reactivity and interactions understanding, while AIM study indicated low hydrogen bond energy and non-covalent interactions potentially influencing chemical behavior.•Molecular docking investigations provided insights into interactions with α-glucosidase and α-amylase proteins, suggesting novel design possibilities for controlling postprandial glucose levels in diabetes. A library of six novel bis-Schiff base derivatives (2a-f) were synthesized, characterized through modern spectroscopic techniques and screened for their α-glucosidase and α-amylase inhibitory activities (in vitro). In the series, compound 2a (IC50 = 5.64 ± 2.22 µM) and 2f (IC50 = 22.78 ± 2.37 µM) were the most potent α-amylase inhibitors while the remaining four compounds showed significant to less activity. In case of α-glucosidase inhibition, four compounds 2e (IC50 = 2.83 ± 0.18 µM), 2c (IC50 = 7.03 ± 0.15 µM), 2f (IC50 = 9.99 ± 0.20 µM), and 2d (IC50 = 14.68 ± 0.21 µM) displayed excellent inhibitory activity while two compounds showed good inhibitory activity, comparing with the standard acarbose drug. The DFT assay was used to measure the FMO of the synthesized molecules, which indicated their stability, bioactivity and charge transfer. The MEP analysis revealed the distribution of electrostatic potential on the molecular surface of 2a-f, which is helpful for understanding reactivity and interactions. The AIM study showed low hydrogen bond energy and non-covalent interactions. This implies that these molecules may have weak hydrogen bonding and non-covalent interactions, which could affect their chemical behavior. The molecular docking study has provided valuable insights into the interactions between the synthesized derivatives of 2,4-dihydroxyacetophenone with α-glucosidase and α-amylase proteins. The results not only shed light on the binding affinity and ke