Current Topics in Medicinal Chemistry - Volume 15, Issue 9, 2015

Dipyridamole was introduced on the market as coronary vasodilator drug more than half a century ago and is still used as antithrombotic and vasodilator. Among cellular targets, it inhibits phosphodiesterases and raises extracellular levels of adenosine through inhibition of adenosine reuptake by red blood cells. As a consequence, endocellular levels of cyclic nucleotides are upregulated. The rise of cGMP in vascular smooth mu scle cells and of cAMP in platelets provide the mechanism of vasodilation and antithrombosis, which are further potentiated by the release of PGI2 consequent on the increase in endothelial cell cAMP. These effects support the use of dipyridamole in cardiovascular diseases in which the drug is approved for the secondary prevention of cerebrovascular events. On the other hand, dipyridamole has been shown to possess a potent, little perceived, antioxidant activity of potential use in the several fields where pathophysiological pathways are dependent on oxidative stress, including those occurring in atherosclerosis, thrombosis, CNS-related diseases, and cancer.

Coumarins are a large group of substances, primarily of plant origin. Like their more intensively examined congeners flavonoids, many of them are antioxidants. Although such properties may be advantageous in cardiovascular diseases, it has been shown that coumarins exhibit direct effects on the cardiovascular system which are not based on antioxidant activity. The most common example is the well-known drug warfarin, a synthetic compound derived from natural dicoumarol. Moreover, other coumarins have been shown to possess antiplatelet and vasodilatory potential. Interestingly, the former effect may be mediated by the inhibition of various pathways leading to platelet aggregation, their differing effects on those pathways being due to structural differences between the various coumarins. Conversely, their vasodilatory potential is linked in the majority of cases to the inhibition of increases in intracellular calcium concentration in vascular smooth muscle cells, and in several coumarins also to NO-mediated vasodilatation. Available data on both activities are summarized in this review. At the end of this review, relevant data are provided from a few studies testing the in vivo effects of coumarins on major cardiovascular diseases; the clinical use of warfarin and other coumarin anticoagulants, as well as the limited data on the clinical use of coumarins in chronic venous insufficiency and the possible toxicological effects of coumarins.

Tropical parasitic diseases, especially those produced by protozoan parasites, are a major public health problem in many countries, and their impact in the health burden is significant. Oxidative processes proved to be related to these diseases, being the antioxidant agents promising therapeutic solutions for them. Therefore, this review provides an overview of published manuscripts regarding both activities. In particular, the interest of the coumarin derivatives as antioxidant agents with application in parasitic diseases is discussed in this manuscript. The recent findings in this field are highlighted.

Cardiovascular diseases (CVDs) are the major health concern and the leading cause of death. Imbalance between free radicals and anti-oxidant defence is associated with cellular dysfunctions leading to the pathophysiology of various diseases including cardiac and vascular diseases. The stress responsive transcription factor NF-E2-related factor 2/antioxidant response element (Nrf2/ARE) regulates the expression of many detoxifying genes. Nitric oxide (NO) produced by endothelial nitric oxide synthase (eNOS) is an important regulator of vascular function. Involvement of NO in modulating Nrf2 signaling is well established. Thus, it is apparent that increasing NO bioavailability and antioxidant status in vascular and myocardial tissue can be considered as a potential strategy to prevent the onset of vascular dysfunction and CVDs and is therefore of therapeutical interest. Based on the marked protective effect of Nrf2/ARE signalling and intriguing links between antioxidant mechanism and endothelial derived NO, the aim of the present review is to compile conclusive evidence for the involvement of NO-Nrf2/ARE axis in the regulation of cardiovascular function. This review also discusses on improving eNOS and Nrf2 signalling by Nrf2 activators which holds promise for countering cardiac and vascular disorders.

The development of inflammatory immune response is related to an activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-ΚB) signaling. The intracellular molecules from this pathway are sensitive to the alterations in the microenvironment. The changes in cellular redox state, proliferation, gene expression pattern and genomic stability during inflammation induce the activation of non-canonical and atypical NK-ΚB signaling increasing the crosstalk with molecules involved in neddylation, cell cycle checkpoints regulation and DNA repair. This review article describes the reactive oxygen species (ROS)-sensitive kinases from the NF-ΚB pathway and presents the effects of their suppression by small kinase inhibitors. It illustrates that selective targeting of the redox sensor molecules from the inflammatory NK- ΚB cascades can influence cell survival and metabolism as well. We think that this issue is important when evaluating the drug efficacy in clinical studies and their side effects.

Identifying novel therapeutic agents from natural sources and their possible intervention studies has been one of the major areas in biomedical research in recent years. Piper species are highly important - commercially, economically and medicinally. Our groups have been working for more than two decades on the identification and characterization of novel therapeutic lead molecules from Piper species. We have extensively studied the biological activities of various extracts of Piper longum and Piper galeatum, and identified and characterized novel molecules from these species. Using synthetic chemistry, various functional groups of the lead molecules were modified and structure activity relationship (SAR) studies identified synthetic molecules with better efficacy and lower IC50 values. Moreover, the mechanisms of actions of some of these molecules were studied at the molecular level. The objective of this review is to summarize experimental data published from our laboratories and others on antioxidant and anti-inflammatory potentials of Piper species and their chemical constituents.

In recent years, relationship between free radicals and oxidative stress with aging, cancer, atherosclerosis, neurodegenerative disorders, diabetes, and inflammatory diseases became increasingly clear. Confirming the role of oxidants in numerous pathological conditions such as cancer, the antioxidants developed as therapeutics have been proven ineffective. It is well established that melatonin (MLT) and its metabolites are able to function as endogenous free-radical scavengers and broadspectrum antioxidants. Numerous studies also proved the role of MLT and its derivatives in many physiological processes and therapeutic functions, such as the regulation of circadian rhythm and immune functions. The aim of this review is to arouse attention to MLT as a potentially valuable agent in the prevention and/or treatment of some diseases.