Synthesis, characterisation and evaluation of the antidiabetic and antioxidative properties of caffeic acid and ferulic acid-zinc(II) complexes

Abstract

Background: The morbidity and mortality outcomes of diabetes, as well as the associated expenditure on health care remain notable contributors to global socioeconomic burden. The close association to oxidative stress is a major factor aggravating the notoriousness of diabetes, which has been implicated in many complications, as well as the morbidity and mortality outcomes of the disease. Therapeutic approaches with holistic functional profiles and minimal side effects are being explored to manage the disease; approaches that could manage hyperglycaemia and mitigate or reduce the risk of oxidative complications. In this context, supplements and phytochemicals have gained popularity due to their safety profile and numerous biological benefits, including antioxidant functions and beneficial role in glucose and lipid metabolism. In recent years, zinc has been explored as a supplement for diabetes due to its function in insulin integrity and function. On the other hand, natural phenolic acids are known dietary antioxidants with diabetes-related pharmacological potentials. In this study, we took advantage of the insulin mimetic potential of zinc and the antioxidant and pharmacological potentials of ferulic and caffeic acid to develop novel zinc(II) complexes of ferulic and caffeic acid, which demonstrated improved antioxidant and antidiabetic effects. Materials and methods: Zinc sulphate was complexed with ferulic acid, while zinc acetate was complexed with caffeic acid. Zn(II) was complexed with each phenolic acid in a 1:2 mole ratio, respectively. The synthesized complexes were spectroscopically characterized using NMR, FT-IR, high resolution-mass spectroscopy and HP-LC. The cellular toxicity of the complexes was assessed in Chang liver cells and L-myotubes. In vitro, cellular, and isolated tissue models were used to evaluate the antioxidant and antidiabetic properties of the complexes, relative to their precursors. Molecular docking was used to investigate the interaction between the complexes and molecular protein targets that are linked to diabetes. These include GLUT-4, protein kinase B (Akt/PKB), α-glucosidase and α-amylase. The zinc complex of caffeic acid was further subject to in vivo antidiabetic and antioxidant evaluation. Male SD rats were induced with diabetes using 10% fructose and 40 mg/kg bw streptozotocin. Thereafter, the diabetic rats were treated with the Zn(II)-caffeic acid complex and its precursors (caffeic acid and zinc acetate) for 4 weeks at predetermined doses. The effect of the treatments on diabetes and oxidative stress related parameters was measured. Results: Complexation resulted in a bi-caffeic acid-zinc acetate complex and a Zn(II)- biferulate.2H2O complex, thus affording the complexes a moiety of Zn(II) and two moieties of their respective phenolic acids. The complexes showed in vitro radical scavenging, antiglycation, α-glucosidase, α-amylase inhibitory activity that were up to 2.6 folds stronger than that of their precursor phenolic acids. The ability of the complexes to inhibit lipid peroxidation and GSH depletion in hepatocytes was comparable to that of ascorbic acid and up to 3 folds more potent than their precursor phenolic acids. Complexation improved the glucose uptake activity of the phenolic acids in L-6 myotubes and isolated rat muscle tissues. Molecular docking showed the complexes had stronger interaction with the target proteins than their precursor phenolic acids. The complexes were not hepatotoxic and myotoxic. The bi-caffeic acid-zinc acetate complex ameliorated diabetic alterations in diabetic rats. It reduced polyphagia and polydipsia and appreciably recovered weight loss. It increased insulin secretion, insulin sensitivity, hepatic and muscle glycogen, muscle hexokinase activity and Akt phosphorylation, which resulted in improved glucose tolerance and reduced blood glucose in diabetic rats. The complex concomitantly reduced systemic and tissue lipid peroxidation and increased antioxidant enzymes activity in diabetic rats. Notably, the complex outperformed the antidiabetic and antioxidative action of its precursors and had a broader bioactivity profile. Complexing zinc acetate with caffeic acid improved their ameliorative effect on insulin resistance by ∼24 and 42%, respectively, as well as their anti-hyperglycaemic action by ∼24 – 36% and ∼42 – 47%, respectively. In some instances, the antidiabetic action of the complex was comparable to metformin, while its antioxidant effect was better than that of metformin. It is plausible that the two moieties of the phenolic acids in each of the complexes potentiated their improved antioxidant action, while Zn(II) conferred a potent glycaemic control modulatory attribute on the complexes, which suggests a complexation-mediated synergistic potential. Conclusion: Zinc(II) complexation with these phenolic acids may be an alternative approach to improving the efficacy of antidiabetic and antioxidative therapy with minimal adverse or side effects.