Therapeutic potentials of black tea medicaments

Tea; a product of Camellia Sinensis plant is the most broadly used beverage in the world. Tea phytochemicals have been studied for the prevention of various chronic diseases, such as cancer, obesity, diabetes, jaundice, hypertension and inflammation related disorders. Whereas many studies have revealed the potential efficiency of tea for the prevention of these physiological disorders, the underlying mechanisms remain unclear. In this work, we evaluated the evidence and discussed the significance of proposed mechanisms for the prevention of the diseases such as Alzheimer’s, obesity, diabetes mellitus type II, hypertension and asthma by tea. Molecular docking method was used to explore the ability of tea phytochemicals to inhibit the key enzymes. The three dimensional structure of target enzymes were either retrieved from protein data bank or modelled using swiss model. Autodock4.2 software was used for molecular docking that applies Lamarckian Genetic Algorithm. The ligand structures were retrieved from PubChem and KNApSAcK-3D database. PreADMET web server was used for Toxicity and ADME predictions. Based on this analysis, it has been found that theaflavin, rutin and 8-c-ascorbyl epigallocatechin could be the potential lead molecules as they act as inhibitor for most of the target enzymes and has a good drug score and also qualifies the toxicity and ADME test. Further the tea extract is loaded in liposomal drug delivery system and pectin-HEMA hydrogel system to analyse their drug delivery potential and it was found that liposomal system is best suitable for delivery to brain and hydrogel system better serve as colon specific delivery system. We concluded that these phytochemicals or their derivatives can be used for further in-vitro and in-vivo studies to produce valuable lead drug candidates

In vitro pharmacological screening of thiazolidinedione-derivatives on diabetes and Alzheimer’s potential therapeutic targets

There is an increased prevalence of diabetes and other non-communicable diseases in Sub-Saharan Africa and globally. In South Africa, the prevalence of type 2 Diabetes mellitus is currently estimated at 9.0% in people aged 30 and older and is expected to increase. Diabetes-related complications result in acute alterations in the mental state due to poor metabolic control as well as greater rates of decline in cognitive functioning with age, higher prevalence of depression and increased risk of Alzheimer’s disease. Alzheimer’s disease is the most common form of dementia in older adults and possibly contributes to 60 - 70% of cases. Alzheimer’s disease remains incurable, its progression inevitable with the currently available symptomatic therapies being palliative while the treatment of diabetes relies on insulin preparations and other glucose-lowering agents. Current treatment options have numerous side effects such as hypoglycaemia, diarrhoea, weight gain and abnormal liver function. This has geared the investigation of new generations of small molecules which exhibit improved efficacy and safety profiles. On this basis, several studies have shown that thiazolidinediones and their corresponding derivatives exhibit a broad spectrum of biological activities including anti-inflammatory, and antioxidant activities. Furthermore, recent evidence from experimental, epidemiological, and clinical studies highlight the utility of antioxidants for treating diabetes and its complications. Interestingly, there is increasing evidence that links diabetes and Alzheimer’s disease due to their pathophysiology and suppressing glycaemia has been shown to be beneficial in Alzheimer’s disease treatment. Accordingly, the aim of this study, was to evaluate the anti-diabetic and anti-Alzheimer’s properties of four novel synthesized thiazolidinedione-derivatives owing to their antioxidant properties. Methods The aim of this study was achieved through performing ferric reducing antioxidant power activity, 2,2’-Diphenyl-1-Picry Hydrazyl radical scavenging activity, α-amylase inhibition, α-glucosidase inhibition, aldose reductase inhibition, protein tyrosine phosphatase-1B inhibition, dipeptidyl peptidase-4 inhibition, acetylcholinesterase inhibition, matrix metalloproteinase-1 inhibition, and β-amyloid aggregation inhibition assays. In addition, peroxisome proliferator-activated receptor-γ activation was performed through docking studies. To establish physicochemical properties of TZD derivatives investigated, further in-silico studies were done using SwissADME tools. Results To this end, in-vitro and in-silico studies were successfully performed. In-silico ADME profiling predicted these derivatives to be drug-like with moderate to good solubility in the GI and not blood-brain barrier permeable. Furthermore, docking of these molecules against PPARγ predicted a similar mode of action to that of thiazolidinediones using Rosiglitazone as the standard drug with TZDD2 and TZDD4 forming equivalent conformations to that of Rosiglitazone in the same binding site and TZDD3 having an equivalent LBE to that of Rosiglitazone (-8.84 and -8.63kcal/mol respectively). In-vitro evaluation predicted a moderate antioxidant activity with TZDD2 and 3 exhibiting the highest FRAP activity and DPPH radical scavenging activity. Furthermore, enzymatic inhibition assays showed a relative inhibition activity with TZDD3 exhibited > 100% inhibition in concentrations ≥ 30 μg/mL and TZDD1, 2 and 4 exhibited ≥ 50% inhibition activity in all the concentrations (10, 20, 30, 40 and 50 μg/mL) in the α-amylase inhibition assay. Similarly, in the α-glucosidase inhibition assay, all the four derivatives exhibited a concentration dependent activity with TZDD3 showing the most activity. All the four derivatives exhibited ≥ 30% inhibition in the aldose reductase inhibition assay except TZDD1 at 10 μg/mL. TZDD4 exhibited a concentration dependent inhibition activity in the protein tyrosine phosphatase-1B inhibition assay. Interestingly, TZDD3 showed a decreasing inhibition activity as its concentration increased from 10 μg/mL through to 50 μg/mL. In the dipeptidyl peptidase–4 inhibition assay, TZDD2 and TZDD4 exhibited ≥ 20% inhibition activity across all the concentrations and in the acetylcholinesterase assay, TZDD1, 3 and 4 exhibited ≥ 25% across all the concentrations. Interestingly, in the matrix metalloproteinase-1 inhibition assay, some of these derivatives exhibited partial activation activity and partial inhibition with TZDD1 showing activation in concentrations 10 and 20 μg/mL and inhibition in concentrations 30, 40 and 50 μg/mL. TZDD4 showed activation in all the concentrations. In the β-amyloid aggregation assay, all the four derivatives showed inhibition activity ≥ 10% except TZDD1 at 50 μg/mL. Conclusions Diabetes mellitus and Alzheimer’s disease are a type of pathology of global concern, and several researchers worldwide have strived to search for novel therapeutic treatments and prevention for diabetes as well as Alzheimer’s disease. Recent studies provide a direct link v between diabetes mellitus and Alzheimer’s disease, and the need to find novel drugs that can mitigate these two is of increasing interest. In our search for antidiabetic and anti-Alzheimer’s activity, TZD derivatives (TZDD1, TZDD2, TZDD3 and TZDD4) exhibited good antioxidant activity, anti-hyperglycaemic activity and a relatively promising anti-Alzheimer’s activity. This was observed from the in vitro evaluation performed which included α – amylase, α – glucosidase, aldose reductase, PTP1B, DPP4, amyloid β aggregation, and AChE inhibition assays. Furthermore, docking of the derivatives against PPARγ predicted a similar molecular interaction to that of thiazolidinediones using Rosiglitazone as the standard drug. Furthermore, in silico ADME profiling predicted the derivatives to have moderate to good solubility in the GI (good GI bioavailability), and also exhibited excellent drug likeness. However, they are predicted not permeate the BBB. Further in silico studies and in vivo should be conducted to establish toxicities, as well as drug delivery to the brain for effective therapeutic effect against Alzheimer’s disease.Thesis (MSc) -- Faculty of Pharmacy, Pharmacology, 202

Enzymatic inhibitory activity of hydroxycinnamates (HCs): in silico studies

Diabetes is a worldwide health issue that has been expanding mainly in developed countries. It is characterized by abnormal levels of blood sugar due to several factors. The most common are resistance to insulin and the production of defective insulin which exerts little or no effect. Its most common symptoms include tissue damage to several systems due to elevated levels of blood sugar. One of the key enzymes in hydrocarbon metabolism is α-glucosidase (EC 3.2.1.20). It catalyzes the breakdown of complex carbohydrates into their respective monomers (glucose) which allows them to be absorbed. In this work, caffeoyl quinic acids and their metabolites were analyzed as potential inhibitors for α-glucosidase. The search for the best inhibitor was conducted using molecular docking. The affinity of each compound was compared to the inhibitor present in the crystal structure of the protein. As no inhibitor with a similar affinity was´found, a new approach was used, in situ drug design. It was not possible to achieve an inhibitor capable of competing with the one present in the crystal structure of the enzyme, which is also its current commercial inhibitor. It is possible to draw some conclusions as to which functional groups interact best with certain residues of the active site. This work was divided into three main sections. The first section, Diabetes, serves as an introduction to what is Diabetes, its symptoms and/or side effects and how caffeoyl quinic acids could be used as a treatment. The second section, Caffeoylquinic acids and their metabolites as inhibitors for Alfa-glucosidase, corresponds to the search through molecular docking of caffeoyl quinic acids as inhibitors for α-glucosidase and what was possible to draw from this search. The last section, In situ design of an inhibitor for α-glucosidase (EC 3.2.1.20), corresponds to the in situ drug design study and what it achieved. The representation of each of the molecules used as a ligand can be found in the Annexes.Universidade da Madeir

Biosynthesis and Biological Activity of Carbasugars

The first synthesis of carbasugars, compounds in which the ring oxygen of a monosaccharide had been replaced by a methylene moiety, was described in 1966 by Prof. G.E. McCasland’s group. Seven years later, the first true natural carbasugar (5a-carba-R-D-galactopyranose) was isolated from a fermentation broth of Streptomyces sp. MA-4145. In the following decades, the chemistry and biology of carbasugars have been extensively studied. Most of these compounds show interesting biological properties, especially enzymatic inhibitory activities and, in consequence, an important number of analogues have also been prepared in the search for improved biological activities. The aim of this review is to give coverage on the progress made in two important aspects of these compounds: the elucidation of their biosynthesis and the consideration of their biological properties, including the extensively studied carbapyranoses as well as the much less studied carbafuranoses

STARCH HYDROLASE INHIBITORS FROM TROPICAL BOTANICALS: METHODOLOGY, HIGH THROUGHPUT SCREENING AND SYNERGY

Ph.DDOCTOR OF PHILOSOPH