Current Topics in Medicinal Chemistry - Volume 16, Issue 23, 2016

The use of natural products for the treatment of disease is one of the oldest cultures exists. Currently, the research of new drugs using natural products shows a poorly explored biodiversity and a great interest of marketing. The enzymatic inhibition by some natural products is investigated among these is the inhibition of hyaluronidase and the consequent reduction of the degradation of hyaluronic acid. So there is a reduction of inflammation and angiogenesis. This study reports the main natural species studied in inhibiting human hyaluronidase that can be the subject of future research for new drugs.

Diabetes is a major chronic metabolic disorder globally and around of 285 million people are affected by the disease and the number is expected to double in the next two decades. The major focus of anti-diabetic therapies is to enhance insulin production, sensitivity and/or reduce the blood glucose level. Although several synthetic drugs have been developed as antidiabetic agents but their utility has been hampered due to their side effects and poor efficacy. In this scenario, research on natural products has been gained importance due their safety profile in toxicity studies. Terpenoids belong to an important class of natural products and several terpenoids have been reported as antidiabetic agents. Some of them are under various stages of pre-clinical and clinical evaluation to develop them as antidiabetic agents. These agents can inhibit enzymes responsible for the development of insulin resistance, normalization of plasma glucose and insulin levels and glucose metabolism. Triterpenes can act as promising agents in the treatment of diabetic retinopathy, neuropathy and nephropathy or in impaired wound healing by inhibiting several pathways involved in the diabetes and associated complications. However, efforts in understanding the biological actions and clinical studies involving the applications of triterpenes in treating diabetes are very limited. Hence, special attention is imperative to explore the therapeutic potential of these compounds and provide new information to the scientific community. This review aims to provide the recent advances in triterpenes chemistry, its derivatives, biological interventions and its therapeutic applications with special emphasis on diabetes and its associated disorders.

In inflammatory bowel disease (IBD) patients, the enzyme phospholipase A2 (PLA2) is overexpressed in the inflamed intestinal tissue, and hence may be exploited as a prodrug-activating enzyme allowing drug targeting to the site(s) of gut inflammation. The purpose of this work was to develop powerful modern computational approaches, to allow optimized a-priori design of phospholipid (PL) based prodrugs for IBD drug targeting. We performed simulations that predict the activation of PL-drug conjugates by PLA2 with both human and bee venom PLA2. The calculated results correlated well with in-vitro experimental data. In conclusion, a-priori drug design using a computational approach complements and extends experimentally derived data, and may improve resource utilization and speed drug development.

Background: Natural products are characterized by their chemical diversity and being a good source of a range of bioactive structures including antidiabetic compounds. Diabetes mellitus (DM) is considered a major worldwide health concern. Rational drug design has been widely accomplished, to discover and optimize innovative leads for different molecular targets of type 2 DM including α-glucosidase, PPARγ, DPP-IV, PTP1B, AR, GSK-3β, 11β-HSD1, GK, etc. Objective: This review illustrates the potential of natural products as a rich source of lead compounds for antidiabetic drug discovery with some examples of computational studies carried out to determine the possible molecular target, structure activity relationship, and further optimization chances. Conclusion: Natural products will remain an attractive source for researchers to explore their therapeutic potential against DM. Guided by the computational studies; systematic lead optimization via structural modifications will speed up the generation of potential new clinical candidates for the treatment of type 2 DM.

Cytokinin nucleosides exhibit antitumor, antiviral, antiprotozoal, blood pressure reducing, anti-inflammatory, and antipsychotic activity. These compounds also influence platelet aggregation and exhibit some other biological activities. Cytokinins are N6-substituted adenines and represent an important group of phytohormones with diverse biochemical functions in plants, stimulating cell division and plant growth. The main structural feature of cytokinin nucleosides is the presence of a hydrophobic hydrocarbon moiety at the N6-position of adenosine. This moiety is responsible for a difference in physicochemical and biological properties as compared to adenosine. 1-N-Tuberculosinyladenosine and N6-tuberculosinyladenosine are specifically produced by Mycobacterium tuberculosis as components of the plasmatic membrane, thus making them attractive targets for clinical test development. Structurally related compounds were found in marine organisms. It has been shown also that tRNA contains N6-isoprenyladenosine and some other related compounds. This review summarizes the structural features, biological activity, and the synthesis of cytokinin nucleosides and some of their closely related derivatives such as cytokinins and terpene derivatives of adenine.

Obesity is a global health threat. OECD reported that more than half (52%) of the adult population in the European Union is overweight or obese. Obesity and obesity-related co-morbidities have deep negative effects on morbidity, mortality, professional and personal quality of life. Healthcare costs represent a negative impact of this disease, with an associated economic cost of 100 billion US$ per year in the United States. The most prescribed drugs for obesity treatment worldwide are orlistat, and phentermine/topiramate extended release, while the major prescribed drug for the same disease in the US are exenatide and dapagliflozin. The so far developed drugs, targeting weight loss, have a long history of malignant secondary effects. There is still a lack of efficient and safe drugs to treat obesity and related metabolic complications since in many cases cure cannot be reached by bariatric surgery or healthy lifestyle habits. Terrestrial and aquatic organisms are a promising source of valuable, bioactive compounds, often with interest for human health. Some of the natural compounds or organisms have been used for centuries by humans as traditional medicine foods. In this review, we give insights into the adipose tissue function and development, and the progress in traditional anti-obesity pharmacotherapy. A major focus is to highlight the state of the art of natural compounds with anti-obesity properties and their potential as candidates for drug development; an overview is given about natural compounds derived from different marine animal sources, cyanobacteria, marine phytoplankton, fungus or plants.

Lipid metabolic disorder refers to the dyslipidemia in the plasma. Abnormal working or lipid metabolism process leads to supernormal increase of one or multi kinds of lipids in plasma. It is a significant risk factor for many diseases and has become a serious danger to the mankind health. The clinical drugs adjusting lipid levels have a great variety in the market, side effects and adverse reactions. Meanwhile, many Chinese herbal medicines and natural medicines have the unnegligible role of regulating lipid metabolism, which become the research focus of medical workers in past decades. With advantages of fewer side effects, abundant resources and multi-target functions, terrestrial and marine bioactive constituents are proved as one of the important sources of the lead compounds in drug discovery and have been widely applied in the treatment and prevention of lipid metabolic diseases. In this paper, the recent advancements and current status of natural medicinal ingredients mainly based on lipid-lowering activities were reviewed in detail. Moreover, their bioactivity screening and important mechanisms in hyperlipemia progression were summarized and compared. It was also selectively introduced about related structural modification and new drug development on the basis of promising lead compounds. Finally, the current problems and possible prospects of natural constituents against lipid metabolism disorder in the future were discussed.

Acarbose, a well known and efficacious α-amylase and α-glucosidase inhibitor, is a postprandial acting antidiabetic drug. DNS-based α-amylase inhibitory assays showed that use of acarbose at concentrations above 125 μg/ml resulted in release of reducing sugar in the reaction, an unexpected observation. Objective of the present study was to design experimental strategies to address this unusual finding. Acarbose was found to be susceptible to thermo-lysis. Further, besides being an inhibitor, it could also be hydrolyzed by porcine pancreatic α-amylase, but had weaker affinity for α - amylase compared to starch. GRIP docking was done for the mechanistic analysis of the active site in the enzyme for substrate, inhibitor and, inhibitor’s metabolite (K2). Interaction between acarbose and α-amylase involved significant hydrogen binding compared to that of starch, producing a stronger enzyme-inhibitor complex. Further, docking analysis led us to predict the site on α-amylase where the inhibitor (acarbose) bound more tightly, which possibly affected the binding and hydrolysis of starch exerting its effective anti-diabetic function.