Curcumin (bis-α,β-unsaturated β-diketone) plays an important role in the prevention of numerous diseases, including diabetes. Curcumin, as an enzyme inhibitor, has ideal structural properties including hydrophobic nature, flexible backbone, and several available hydrogen bond (H-bond) donors and acceptors. In this study, curcumin-fused aldohexose derivatives 3(a-c) were synthesized and used as influential agents in the treatment of diabetes with inhibitory properties against two carbohydrate-hydrolyzing enzymes α-glucosidase (α-Gls) and α-amylase (α-Amy) which are known to be significant therapeutic targets for the reduction of postprandial hyperglycemia. These compounds were isolated, purified, and then spectrally characterized via FT-IR, Mass, 1H, and 13C NMR, which strongly confirmed the targeted product's formation. Also, their inhibitory properties against α-Gls and α-Amy were evaluated spectroscopically. The Results indicated that all compounds strongly inhibited α-Amy and α-Gls by mixed and competitive mechanisms, respectively. The intrinsic fluorescence of α-Amy was quenched by the interaction with compounds 1 and 3b through a dynamic quenching mechanism, and the 1 and 3b/α-Amy complexes were spontaneously formed, mainly driven by the hydrophobic interaction and hydrogen bonding. Fourier transform infrared spectra (FT-IR) comprehensively verified that the binding of compounds 1 and 3b to α-Amy would change the conformation and microenvironment of α-Amy, thereby inhibiting the enzyme activity. Docking and molecular dynamics (MD) simulations showed that all compounds interacted with amino acid residues located in the active pocket site of the proteins. In vivo studies confirmed the plasma glucose diminution after the administration of compound 3b to Wistar rats. Accordingly, the results of the current work may prompt the scientific communities to investigate the possibility of compound 3b application in the clinic.
Keywords: Blood glucose; Curcumin; Diabetes mellitus; Hyperglycemia; α-Amylase; α-Glucosidase.
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