Mini Reviews in Medicinal Chemistry - Volume 15, Issue 10, 2015

The enzyme arginase catalyses the divalent cation dependent hydrolysis of L-arginine to produce L-ornithine and urea. Two isoforms of arginases have been identified in mammalian (including human) cells. Moreover, some infectious pathogens (e.g. Leishmania) synthesize their own arginase. Work over the last decades has revealed that elevated arginase activity both decreases cellular availability in nitric oxide (NO) by competing with NO synthases (NOS) and increases concentration in L-ornithine, a precursor in the biosynthesis of polyamines which are important for cell differentiation and proliferation. From these data emerged the concept that selective arginase inhibitors might be a valuable strategy for treatment of various diseases associated with decreased NO and/or increased polyamines production. Consistent with this, recent research provides compelling evidence supporting the beneficial effects of arginase inhibitors in cardiovascular diseases (hypertension, ischemia reperfusion injury, atherosclerosis, diabetes mellitus), asthma, cancer, immunologically-mediated diseases or leishmaniasis. Despite active programs to identify potent arginase inhibitors, effective chemical compounds with reliable pharmacokinetics and toxicological properties are rare. The present review summarizes available data on the discovery of new arginase inhibitors from natural origin. Current knowledge on plant-derived compounds or extracts with arginase inhibitory properties as well as available data on structure-activity relationship (SAR) will be presented. Lastly, the present review will open up new prospects in order to improve the discovery of novel arginase inhibitors from natural sources.

Malaria is one of the most important tropical diseases since more than 40% of the world population is at risk. This disease is endemic to more than 100 nations and remains one of the main leading causes of death in children less than five years of age worldwide. Natural product-derived compounds have played a major role in drug discovery, often as prototypes to obtain more active semi synthetic derivatives. Antimalarial pharmacotherapy is a significant example of plant-derived medicines, such as quinine and artemisinin. This review highlights studies on terpenes and their semi synthetic derivatives from natural sources with antimalarial activity reported in the literature during eleven years (2002-2013). A total of 114 compounds are found among terpenes and their semi synthetic derivatives. Cytotoxicity of the compounds is also found in this review. Furthermore, the physicochemical properties of the terpenes addressed are discussed based on seven well established descriptors, which provide a useful source for the elaboration of a terpene library of antimalarial compounds.

Cancer is a serious disease characterized by the uncontrolled growth division of cells, and nowadays it remains a significant challenge for the medical field. Malaria is an infectious disease in the similar situation to cancer. Almost 40% people in the world live in areas with malaria risk and each year there are about 2 to 3 million people dying from malaria. Farnesyltransferase (FTase) that belongs to isoprenyltransferase family can catalyze the initial step of Ras-processing and is identified as a promising target for the treatment of cancer and malaria. During the past decade years, a large number of FTase inhibitors with anticancer or antimalarial activity have been reported and some of them are undergoing clinical development. This review mainly introduces the FTase inhibitors as anticancer and antimalarial agents, with focus on their enzyme inhibitory activity, stability and enzyme selectivity, etc. In particular, the promising new FTase inhibitors among them will be discussed in detail and the inspirations for their design will be highlighted.

The success of an oral drug route administration depends on many factors that interfere in its bioavailability, therapeutic efficacy and clinical safety. In human cells, ATP-dependent efflux transporter proteins, such as P-glycoprotein (P-gp), BCRP and MRP2, reduce the absorption of drugs. A tiered approach chosen to evaluate drugs as substrates or inhibitors of efflux pumps, particularly P-gp, should be carefully selected, since each study method has advantages and intrinsic limitations to their processes. Depending on the adopted study conditions, the results may not correspond to the real characteristics of the drug regarding to its modulation by specific efflux proteins. This mini-review aims at summarizing the role of P-gp in the drugs oral absorption and correlating some of the most used permeability methods to determine the drug condition as P-gp substrate. Studies about P-gp have shown that it is a dynamic protein, facilitating secretion of endogenous compounds, as aldosterone, and protecting cells against xenobiotics. Different efflux assays are employed to evaluate drugs as P-gp substrates. In an initial planning, MDCK-MDR1 tend to be the chosen method for efflux studies due its ability of express P-gp, followed by studies conducted in Caco-2 models. However, it is necessary to evaluate the advantages and disadvantages of each method to generate sound results and to set the correlation in vitro x in situ x in vivo.

Recently, the concept of functional food can be seen worldwide, and there are several local wisdoms on health–conscious. In this context, the protein fractionation of\milk has attracted interests. Casein-derived bioactives have been identified as showing several health beneficial bioactivities including opiate, antithrombotic, antioxidative, antimicrobial, osteoprotective, anticariogenic and growth–promoting. Peptides have to be absorbed from the intestine and reach the target cells in sufficient concentrations or act via receptors; then they can show health effects. In this review paper, the milk–derived peptides and their therapeutic effects are introduced. Also the opiate and antithrombotic effects of these peptides are described.