Open Medicinal Chemistry Journal最新文献

ChemVassa, a new chemical structure search technology, was developed to allow rapid in silico screening of compounds for hit and hit-to-lead identification in drug development. It functions by using a novel type of molecular descriptor that examines, in part, the structure of the small molecule undergoing analysis, yielding its "information signature." This descriptor takes into account the atoms, bonds, and their positions in 3-dimensional space. For the present study, a database of ChemVassa molecular descriptors was generated for nearly 16 million compounds (from the ZINC database and other compound sources), then an algorithm was developed that allows rapid similarity searching of the database using a query molecular descriptor (e.g., the signature of atorvastatin, below). A scoring metric then allowed ranking of the search results. We used these tools to search a subset of drug-like molecules using the signature of a commercially successful statin, atorvastatin (Lipitor™). The search identified ten novel compounds, two of which have been demonstrated to interact with HMG-CoA reductase, the macromolecular target of atorvastatin. In particular, one compound discussed in the results section tested successfully with an IC50 of less than 100uM and a completely novel structure relative to known inhibitors. Interactions were validated using computational molecular docking and an Hmg-CoA reductase activity assay. The rapidity and low cost of the methodology, and the novel structure of the interactors, suggests this is a highly favorable new method for hit generation.

The cyclooxygenase-2 (COX-2) enzyme binds to arachidonic acid resulting in the release of metabolites that induce pain and inflammatory responses. Recent studies have shown that strong COX-2 expression is highly correlated with increased tumor risk. Therefore, the development of potent COX-2 inhibitors to relieve pain and treat cancers requires further investigation. We used virtual screening to find three COX-2 inhibitors (Phar-95239, T0511-4424 and Zu- 4280011) from a huge zinc database containing 2000000 compounds. The effects of the compounds on COX-2 were compared to those on COX-1 using a colorimetric COX (ovine) screening assay kit. The selectivity index, the ratio of IC(50) for COX-1 inhibition to that of COX-2, calculated were MTT assay was used to evaluate the cytotoxic activity of the compounds using different dilutions. The IC(50) values were calculated. Based on the results of the MTT assay, the IC(50) values for compounds Phar-95239, T0511-4424 and Zu-4280011 were 178.52, 143 and 97.61 µM, respectively, and the selectivity indices of the compounds were 11.36, 12.20 and 20.03, respectively. These results indicated a relationship between the selectivity index and anticancer activity. Zu-4280011 displayed the highest selectivity index and the best results in the MTT assay among selected componds.

Peroxisome proliferator-activated receptor (PPAR) agonists are used as adjunct therapy in the treatment of diabetes mellitus. Fibrates, including fenofibrate, gemfibrozil, benzafibrate, ciprofibrate, and clofibrate act on PPAR alpha to reduce the level of hypertriglyceridemia. However, agonists (ligands) of PPAR-beta/delta receptors, such as tesaglitazar, muraglitazar, ragaglitazar, imiglitazar, aleglitazar, alter the body's energy substrate preference from glucose to lipids and hence contribute to the reduction of blood glucose level. Glitazones or thiazolidinediones on the other hand, bind to PPAR-gamma receptors located in the nuclei of cells. Activation of PPAR-gamma receptors leads to a decrease in insulin resistance and modification of adipocyte metabolism. They reduce hyperlipidaemia by increasing the level of ATP-binding cassette A1, which modifies extra-hepatic cholesterol into HDL. Dual or pan PPAR ligands stimulate two or more isoforms of PPAR and thereby reduce insulin resistance and prevent short- and long-term complications of diabetes including micro-and macroangiopathy and atherosclerosis, which are caused by deposition of cholesterol. This review examines the chemical structure, actions, side effects and future prospects of dual and pan PPAR agonists.

Amylin, (islet amyloid polypeptide) or diabetes-associated peptide is co-secreted with insulin in the islet of Langerhans of diabetic patients in approximately 1:100, amylin-insulin ratio. The soluble form of amylin, an analogue of amylin, is used as a supplement to insulin in the treatment of type 1 diabetes. Co-administration of amylin analogue with insulin to patients with type 1 diabetes induced a larger reduction in proprandial hyperglycemia, with a concomitant reduction in the level of glucagon when compared to insulin monotherapy. The actions of amylin analogues appear to be synergistic to insulin, with which it is co-released from insulin-producing beta cells after a meal. Amylin analogues such as pramlintide has been shown to significantly reduce body weight, HbA1c values and even the dosage of insulin. A moderate weight loss can also be achieved in obese patients with or without diabetes. A major side effect of some amylin analogues includes nausea and excitation of the area postrema. This review examines the medicinal chemistry of amylin and its analogues and their effects.

Chagas disease (CD), caused by the intracellular protozoan Trypanosoma cruzi, is a parasitic illness endemic in Latin America. In the centennial after CD discovery by Carlos Chagas (1909), although it still represents an important public health problem in these affected areas, the existing chemotherapy, based on benznidazole and nifurtimox (both introduced more than four decades ago), is far from being considered ideal due to substantial toxicity, variable effect on different parasite stocks and well-known poor activity on the chronic phase. CD is considered one of the major "neglected" diseases of the world, as commercial incentives are very limited to guarantee investments for developing and discovering novel drugs. In this context, our group has been pursuing, over the last years, the efficacy, selectivity, toxicity, cellular targets and mechanisms of action of new potential anti-T. cruzi candidates screened from an in-house compound library of different research groups in the area of medicinal chemistry. A brief review regarding these studies will be discussed, mainly related to the effect on T. cruzi of (i) diamidines and related compounds, (ii) natural naphthoquinone derivatives, and (iii) megazol derivatives.

The 3,5-disubstituted tetrahydro-2H-1,3,5-thiadiazine-2-thione scaffold have found many applications in recent years. This review is aimed at highlighting the most important aspects about these compounds: synthesis, spectroscopic characterization and antiprotozoan activities. How the chemical nature of N-substituents influences the overall activity / cytotoxicity profile will also be discussed.

Since emergence of chloroquine-resistant Plasmodium falciparum and reports of parasite resistance to alternative drugs, there has been renewed interest in the antimalarial activity of acridines and their congeners, the acridinones. This article presents literature compilation of natural acridinone alkaloids and synthetic 9-substituted acridines, acridinediones, haloalcoxyacridinones and 10-N-substituted acridinones with antimalarial activity. The review also provides an outlook to antimalarial modes of action of some described compounds.

Diabetes mellitus (DM) is one of the oldest known human disease currently affecting more than 200 million people worldwide. Diabetes mellitus is derived from two Greek words meaning siphon and sugar. In DM, patients have high blood level of glucose and this passes out with urine. This is because the endocrine pancreas does not produce either or not enough insulin or the insulin which is produced is not exerting its biochemical effect (or insulin resistance) effectively. Insulin is a major metabolic hormone which has numerous functions in the body and one main role is to stimulate glucose uptake into body's cells where it is utilized to provide energy. The disease is classified into type 1 and type 2 DM. Type 1 DM develops when the insulin producing β cells have been destroyed and are unable to produce insulin. This is very common in children and is treated with insulin. Type 2 DM (T2DM) develops when the body is unable to produce an adequate amount of insulin or the insulin which is provided does not work efficiently. This is due to life style habits including unhealthy diet, obesity, lack of exercise and hereditary and environmental factors. Some symptoms of DM include excess urination, constant thirst, lethargy, weight loss, itching, decreased digestive enzyme secretion, slow wound healing and other related symptoms. If left untreated, DM can result in severe long-term complications such as kidney and heart failure, stroke, blindness, nerve damage, exocrine glands insufficiency and other forms of complications. T2DM can be treated and controlled by prescribed drugs, regular exercise, diet (including some plant-based food) and general change in life style habits. This review is concerned with the role of plant-based medicine to treat DM. One such plant is Momordica charantia which is grown in tropical countries worldwide and it has been used as a traditional herbal medicine for thousands of years although its origin in unknown. This review examines the medicinal chemistry and use(s) of M. charantia and its various extracts and compounds, their biochemical properties and how they act as anti-diabetic (hypoglycemic) drugs and the various mechanisms by which they exert their beneficial effects in controlling and treating DM.

Diabetes mellitus (DM) is a major metabolic disorder currently affecting over 200 million people worldwide. Approximately 90% of all diabetic patients suffer from Type 2 diabetes mellitus (T2DM). The world's economy coughs out billions of dollars annually to diagnose, treat and manage patients with diabetes. It has been shown that the naturally occurring gut hormones incretins, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) can preserve the morphology and function of pancreatic beta cell. In addition, GIP and GLP-1 act on insulin receptors to facilitate insulin-receptor binding, resulting in optimal glucose metabolism. This review examines the medicinal chemistry and roles of incretins, specifically, GLP-1 and drugs which can mimic its actions and prevent its enzymatic degradation. The review discussed GLP-1 agonists such as exenatide, liraglutide, taspoglutide and albiglutide. The paper also identified and reviewed a number of inhibitors, which can block dipeptidyl peptidase 4 (DPP-4), the enzyme responsible for the rapid degradation of GLP-1. These DPP-4 inhibitors include sitagliptin, saxagliptin, vildagliptin and many others which are still in the experimental phase.