Zinc(II) mineral increased the in vitro, cellular and ex vivo antihyperglycemic and antioxidative pharmacological profile of p-hydroxybenzoic acid upon complexation

Abstract

In this study, zinc was complexed with p-hydroxybenzoic acid to synthesize a complex with improved pharmacological profile. Proton NMR and FTIR analysis were used to characterize the complex. Several in vitro, cellular and ex vivo antihyperglycemic and antioxidative assays were used to evaluate the potency of the complex, relative to its precursors, while molecular docking was used to investigate interactions with insulin signaling targets (GLUT-4 and PKB). Also, the cytotoxicity of the complex was evaluated in Chang liver cells and L-6 myotubes using MTT assay. Complexation was through a Zn(O₄ ) coordination. This afforded the complex two moieties of p-hydroxybenzoic acid, which influenced its activities. While the complex retained the α-glucosidase and α-amylase inhibitory activity of its phenolic acid precursor, complexation increased in vitro and ex vivo antioxidant activity of the phenolic acid by 1.4 to 10.5-folds. Complexation, further, conferred a potent antiglycation activity and L-6 myotube and psoas muscle glucose uptake properties (2.1 to 3.5-folds more than p-hydroxybenzoic acid) on the phenolic acid, without notably inhibiting or reducing the viability of Chang liver cells (IC₅₀ = 5,120 μM) and L-6 myotubes (IC₅₀ = 2,172 μM). Docking studies showed the complex had better interactions with insulin signaling targets (GLUT-4 and PKB) than p-hydrobenzoic acid, which may influence its glucose uptake effects. Data suggest that Zn(II) complexation improved and/or broadened the pharmacological profile of p-hydroxybenzoic acid, thus, may be further studied as a promising adjuvant for phenolic acids. PRACTICAL APPLICATIONS: Most antidiabetic drugs are used as two or more combinations to achieve better efficacy, which may cause drug interaction and increase the risk of side effects associated with these drugs. This study takes advantage of the glycemic control property of zinc and the antioxidant and/or diabetes-related pharmacological properties of p-hydroxybenzoic acid to form a complex with improved and broader antioxidant and antihyperglycemic profile and minimal toxicity concerns. With appropriate further studies, Zn(II)-phenolic acid complexes may be safe nutraceuticals for diabetes and related oxidative complications.

Keywords: Zn(II)- p-hydroxybenzoic acid complex; antioxidant; diabetes; glucose uptake; p-hydroxybenzoic acid; zinc mineral.