Abstract

Background: The role of zinc in diabetes has been a subject of considerable interest due to the insulin-mimetic properties associated with this mineral. On the other hand, phenolic acids are known as plant-derived polyphenols with antioxidative and antidiabetic pharmacological credence.

Objective: This study was conducted in order to develop a novel therapeutic nutraceutical with an improved and multi-mode antidiabetic and antioxidative pharmacological property using cinnamic acid and Zn(II) mineral framework.

Methods: A Zn(II) acetate complex of cinnamic acid was synthesized and characterized using FT-IR and ¹HNMR spectroscopy. Cytotoxicity evaluation was done using Chang liver cells and differentiated L6 myotubes. DPPH and ABTS scavenging, as well as Fe³⁺ reducing effects, were used to evaluate the antioxidant capacity. The antiglycation, as well as α-glucosidase and α-amylase inhibitory properties, were evaluated. Insulin mimetic property was evaluated as glucose uptake in L6 myotubes, while the complex was docked against GLUT-4 and PKB.

Results: FTIR and ¹HMR suggested that Zn(II) complexed with cinnamic acid through a Zn(O₄) coordination mode, thus affording the resulting complex 2 cinnamic acid molecules. Hence, complexation increased (p ˂ 0.05) the antiglycation effect of cinnamic acid (IC₅₀ = 29.3 μM) by 2 folds (IC₅₀ = 13.9 μM). Also, Zn(II) conferred a potent glucose uptake (EC₅₀ = 31 μM) and α-glucosidase inhibitory (IC₅₀ = 59.4 μM) property on cinnamic acid; hence the activity of the complex was 162 and 2.1 folds higher than (p ˂ 0.05) its precursor, respectively. Further molecular docking studies showed that the complex had a stronger interaction with insulin signaling proteins (GLUT-4 and PKB) than its precursor. Interestingly, the complex showed no severe cytotoxicity.

Conclusion: Data suggested a structure-activity relationship. Complexation of Zn(II) to cinnamic acid resulted in a complex with improved and multi-facet pharmacological effects, which may be further studied as a safe glycemic control nutraceutical for T2D and glycation-induced complications.

Keywords: Zinc(II) acetate, cinnamic acid, Zn(II) complex, diabetes, glucose uptake, glycation.

Graphical Abstract