Zinc (Ii)-Vanillic Acid Complex: Synthesis, Characterisation And Evaluation Of Antidiabetic And Antioxidative Properties

Abstract

Background: Diabetes is a major non-communicable disease that contributes to morbidity and mortality outcomes, globally. The morbidity and mortality outcomes of diabetes has been attributed to several vascular complications associated with the disease. Oxidative stress has been implicated in several mechanisms underlying the development and progression of diabetic complication. Blood glucose-lowering drugs are commonly used to manage diabetes and mitigate the development of vascular complication. However, many of these antidiabetic drugs have been associated with several unpleasant side effects, which have, somehow, discouraged their use. Moreover, some of these antidiabetic drugs are not affordable to most people in under-developed or developing countries, especially those in the middle- and low-income communities. Supplements and medicinal plants are, however, gaining attention in the prevention and management of many diseases, including diabetes and oxidative stress, perhaps due to their perceived holistic medicinal profile and minimal safety concern. In fact, studies have given credence to the antidiabetic and antioxidative pharmacological potentials of plant-derived phenolics. Vanillic acid is a natural phenolic acid with documented oxidative stress and diabetes related pharmacological properties. Also, zinc mineral has been reported to have insulin mimetic potentials. Data from clinical trials suggest that zinc may be useful in glycaemic control, as well as in diabetes prevention and management. Zn(II) has been complexed with many ligands, to develop potent antidiabetic agents. However, it has been mostly complexed with synthetic organic ligands that has potential toxic effects and little or no reported pharmacological property. In fact, antioxidant ligands such as natural phenolic acids have been scarcely studies as possible ligands of bioactive Zn(II) complexes, despite the minimal toxicity concerns of natural phenolic acids. Specifically, vanillic acid has not been studied as possible ligand to develop a bioactive Zn(II) complex. Therefore, the aim of this study was to synthesize and evaluate the antioxidative and antihyperglycaemic effects of a novel Zn(II)-vanillic acid complex. Materials and methods: Zn(II)-vanillic acid complex was synthesised from zinc sulphate heptahydrate and vanillic acid precursors. After synthesis, the complex was characterised using Fourier-transform infrared (FT-IR) and proton nuclear magnetic resonance (1H NMR) spectroscopic techniques. The effect of the complex on the viability of Chang liver cells and L-6 myotubes was evaluated. Then, different in vitro, cellular and ex vivo experimental models were used to measure the antihyperglycaemic and antioxidative activity of the complex, which was compared to the activity of the complex’s precursors. The in vitro 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS) radicals scavenging and ferric reducing antioxidant activities of the complex and precursors were measured. Also, the inhibitory activity of the test samples on ⍺-glucosidase, ⍺-amylase and glycation activities was measured in vitro. The effect of the test samples on glucose uptake was measured in L-6 myotubes and isolated rat psoas muscle tissue. Finally, the anti-lipid peroxidative effect of the test samples was measured in isolated rat liver tissues induced with oxidative stress. Results and discussion: FT-IR and NMR data suggest that vanillic acid complexed with Zn(II) through a Zn(O6) coordination mode by using its carboxylic functional group. Thus, it is proposed that the complex has three moieties of vanillic acid. This structural property of the complex appears to influence its activity relative to vanillic acid. The DPPH (IC50 = 95.9 μM) and ABTS (IC50 = 12.2 μM) radicals scavenging and Fe3+ reducing (251 mmol/mol AAE at 40 μM) activities of the complex were, respectively, 2.3 (p ˂ 0.05), 1.8 and 1.5 (p ˂ 0.05) folds stronger than those of vanillic acid. Also, the anti-lipid peroxidative activity of the complex (IC50 = 667 μM) in rat liver tissue was 9.7 folds more potent (p ˂ 0.05) than that of vanillic acid (IC50 = 6470 μM) and statistically comparable to that of ascorbic acid standard. Complexing Zn(II) with vanillic acid resulted in a complex with stronger α-glucosidase (IC50 = 48.3 μM; p ˂ 0.05), amylase (IC50 = 5.86) and glycation (IC50 = 19.8 μM) inhibitory activities relative to those of vanillic acid. The potent activity of the complex may be partly attributed to its three vanillic acid moiety, which can collectively potentiate stronger activities compared to vanillic acid alone. Zn(II) conferred potent L-6 myotube (EC50 = 20.4 μM) and muscle tissue (EC50 = 612 μM) glucose uptake effects on vanillic acid. Cytotoxicity data showed that the complex did not reduced the viability of L-6 myotubes and Chang liver cells, suggesting it may not pose hepatotoxicity concerns. Conclusion: Data of this study showed that complexing Zn(II) with vanillic acid resulted in a complex with improved antioxidant and antihyperglycaemic activity relative to vanillic acid. Zn(II) may be further studied as potential adjuvant for vanillic acid in developing bioactive antidiabetic and antioxidative nutraceutical for prevention and management of diabetes and oxidative complications.