Complexation potentiated promising anti‐diabetic and anti‐oxidative synergism between ZN(ii) and ferulic acid: A multimode study

Abstract Aim This study was done to investigate the anti‐diabetic and anti‐oxidative synergism between zinc(II) and ferulic acid through complexation. Methods Zinc sulphate was complexed with ferulic acid in a 1:2 molar ratio. The complex was characterized using Fourier‐transform infrared spectroscopy, proton NMR and high‐resolution mass spectroscopy techniques and evaluated for cellular toxicity. In silico, in vitro, cell‐based and tissue experimental models were used to test the anti‐diabetic and anti‐oxidant activities of the complex relative to its precursors. Results A zinc(II)‐biferulate.2H 2 O complex was formed. The in vitro radical scavenging, anti‐lipid peroxidative and α‐glucosidase and α‐amylase inhibitory activity of the complex was 1.7–2.1 folds more potent than ferulic acid. Zn(II) complexation increased the anti‐glycation activity of ferulic acid by 1.5 folds. The complex suppressed lipid peroxidation (IC 50 = 48.6 and 331 μM) and GHS depletion (IC 50 = 33.9 and 33.5 μM) in both Chang liver cells and isolated rat liver tissue. Its activity was 2.3–3.3 folds more potent than ferulic acid and statistically comparable to ascorbic acid. Zn(II) complexation afforded ferulic acid improved glucose uptake activity in L‐6 myotube (EC 50 = 11.7 vs. 45.7 μM) and isolated rat muscle tissue (EC 50 = 501 and 1510 μM). Complexation increased muscle tissue zinc(II) uptake and hexokinase activity. Docking scores of the complex (−7.24 to −8.25 kcal/mol) and ferulic acid (−5.75 to 6.43 kcal/mol) suggest the complex had stronger interaction with protein targets related to diabetes, which may be attributed to the 2 ferulic acid moieties and Zn(II) in the complex. Moreover, muscle tissue showed increased phospho‐Akt/pan‐Akt ratio upon treatment with complex. The complex was not hepatotoxic and myotoxic at in vitro cellular level. Conclusion Zn(II) complexation may be promising therapeutic approach for improving the glycaemic control and anti‐oxidative potential of natural phenolic acids.