Investigating the in-vitro anti-diabetic, anti- Alzheimer and antioxidant activities of Schiff base vanadium complexes

Abstract

Diabetes mellitus (DM) and Alzheimer's disease (AD) characterised by their progressive debilitating effects have secured spots in the list of the leading causes of morbidity and mortality worldwide. Despite intensive research and clinically available drugs, finding a cure to both diseases has remained elusive. Several therapeutic strategies have been developed to manage these diseases but majority of treatment options result in various side effects and are merely management rather than curative therapies. Current oral therapeutic agents used in the treatment of diabetes may be helpful at the initial stages. However, as patients progress towards complete beta cell failure, the efficacy of these oral agents diminishes and dependence on insulin therapy becomes inevitable in other to maintain normoglycemia and prevent diabetic complications. Similarly, the impact of AD therapies on cognitive functions, quality of life and their clinical significance are marginal to non-existent. Common aetiological features of DM and AD have been established and oxidative stress and inflammation are examples of some of common linkages identified. Therefore, this study was conducted to identify possible drug candidates with a potential to target multiple pathways envisaged to bring about the desired therapeutic effect in DM and AD, see the graphical abstract in Appendix 6. This multitarget approach seeks to address drug-related interactions associated with polypharmacy but also seeks to find lead molecules with the potential to provide better pharmacological management compared to conventional therapies. Schiff base vanadium complexes were selected for this study due to their diverse application and reported biological activities. In-vitro studies were augmented with physicochemical and pharmacokinetic predictions to assess the druggability and physicochemical properties of the vanadium complexes, which plays a role in their overall activity, bioavailability and their safety profiles. Molecular docking simulation was carried out where indicated to assess the preliminary mode of action of these Schiff base complexes. The three synthesized Schiff base vanadium complexes at 20, 40, 60, 80 and 100 μg/mL concentrations were evaluated in-vitro for inhibitory activity against α-glucosidase, α-amylase, and dipeptidyl peptidase-4 (DPP-4). These complexes were also evaluated for inhibitory activity against acetylcholinesterase, matrix metalloproteinase-1 (MMP-1) enzymes, advanced glycation end products and beta amyloid aggregation. The antioxidant capabilities of these compounds were also investigated. Reference compounds were used to validate the assay protocols and the data obtained by spectrophotometric/fluorometric analysis were converted to percentage inhibitions. Enzyme kinetic studies were conducted using the Lineweaver Burk plot. One-way ANOVA was performed to test for statistical significance at p value ≤0.05 using GraphPad prism 6. Statistically separate introduction of vanadium complexes showed significant inhibition as measured with α-glucosidase, DPP-4 and antioxidant assays. On the other hand, minimal inhibitory activity was observed for alpha amylase(α-amylase), acetylcholinesterase, beta amyloid aggregation and advanced glycation end products in comparison with the control. In contrast, enzyme activation was observed with MMP-1. The vanadium complexes were predicted to have drug-like characteristics according to Lipinski parameters; however, their predicted gastrointestinal absorption and blood brain barrier permeability was poor as shown by their locations on the boiled egg model and other generated parameters. Of the three investigated vanadium complexes, vanadium complex 3 showed the most potential towards diabetes and Alzheimer's disease. Based on the results obtained it is evident that these complexes show good anti-hyperglycaemic and antioxidant activity with minimal anti-Alzheimer activity. This study provides evidence to suggest that the Schiff base vanadium complexes may be promising candidates to explore in the control and management of hyperglycaemia, oxidative stress related complications. However, their predicted physicochemical properties may hinder their progress to further phases of drug discovery. This calls for further investigation into alternative means to improve their chemical properties to streamline their inhibitory actions towards multiple targets implicated in AD and DM pathogenesis.