Acylhydrazone derivatives of barbituric acid: Synthesis, in vitro α-amylase inhibition, molecular docking, ADMET and DFT analysis

In this study, a new series of acylhydrazones of barbituric acid were successfully synthesized and characterized through mass, 1 H and 13 C NMR spectroscopy. The compounds (4a-f) were assessed for their in vitro α-amylase inhibitory activity, showing potent inhibition with IC 50 values ranging from 2.46 ± 0.28 to 4.19 ± 0.28 μM that are particularly powerful than the reference acarbose (IC 50 = 5.45 ± 0.29 μM). Molecular electrostatic potential (MEP) study exposed that derivatives with more noticeable negative potential regions (4a and 4e) established stronger activity that highlights the status of hydrogen bonding in enzyme binding. Likewise, compounds with greater hydrophobic regions (4d and 4f) displayed improved binding affinity over hydrophobic connections with non-polar residues at the active site of enzyme. The total charge distribution was originated to effect relations with charged amino acid residues. Moreover, molecular docking studies maintained the experimental results by confirming promising hydrogen bonding and hydrophobic links within the α-amylase active site. Together, these consequences propose that the synthesized hydrazone Schiff bases are hopeful candidates for further expansion as potential anti-diabetic agents targeting α-amylase.