Medicinal Chemistry - Volume 10, Issue 7, 2014

Cardiovascular mortality remains the leading cause of death all over the world, despite recent advances in early diagnosis, interventional techniques and pharmacological treatment targeting several risk factors of cardiovascular disease (CVD) [1]. The inflammatory process, as an integral part of the immune system, plays an important role in tissue homeostasis. Atherosclerosis has been identified early as a chronic inflammatory disease, giving another perspective in the nature of CVD and a new field to explore for the scientific community [2]. In this research, inflammatory biomarkers have been a great ally by helping to clarify the pathophysiological mechanisms linking inflammation to CVD and identify novel therapeutic targets [3]. Dyslipidemias, Acute Coronary Syndromes (ACSs), Atrial Fibrillation (AF), Essential Hypertension (HT) and Chronic Heart Failure (CHF) have been chosen for this special issue as some of the “hottest representatives” regarding CVD. The following series of original mini-review papers attempt to summarize the acquired so far knowledge of the relation of inflammation with the aforementioned conditions, evaluate the utility and prospects of the newly discovered mediators of inflammation in CVD and highlight promising anti-inflammatory therapeutic agents. In the first of this series of articles, Papoutsidakis et al. [4] summarize what is known today about the ways inflammation interacts with lipid metabolism and whether there is therapeutic potential in exploiting this interaction. Although inflammation pathways have been shown to play an important role on the road from dyslipidemia to atherogenesis, there is relatively little data on the ways inflammation promotes changes in total cholesterol, HDL, LDL and triglyceride metabolism. There is accumulating evidence that chronic inflammatory states can aggravate atherogenesis not only by directly promoting the formation of atherosclerotic plaque inside coronary vessels but also indirectly, by impairing lipid metabolism towards a more atherogenic profile, while anti-lipidemic therapies have not focused so far in inflammation pathways that could be contributing to the rise in cholesterol and triglyceride levels. Deftereos et al. [5] in a brief and comprehensive review article deal with the role of the innate immune system in the acutely ischemic myocardium. Since originally described in the 1930s the role of inflammation in the setting of acute myocardial infarction has been extensively studied. Myriads of animal models provided critical insight into the pathways governing the inflammatory responses and revealed the role of the innate immune system in initiating and perpetuating those responses. Despite the newly acquired knowledge, success was never met in the clinical field. Today with more than seven million people dying every year from coronary artery disease and with a rapidly increasing pool of heart failure patients as a result of an acute coronary event, it is compelling to identify possible new targets that modify the inflammatory cascades, attenuating tissue damage without affecting tissue healing. AF is the most common chronic arrhythmia and a source of significant morbidity and mortality. In their paper, Giannopoulos et al. [6] focus on the existing evidence supporting the ‘inflammatory’ hypothesis for AF pathophysiology. They also provide a review of potential biomarkers of inflammation in AF and comprehensively refer to therapeutic means that could counteract the full interplay between this arrhythmia and inflammation. Tsounis et al. [7] provide a detailed review of the current literature on the most important and most studied traditional and novel inflammation markers in HT. Recent evidence suggests that the immune system and inflammation processes are important contributors in the pathophysiology of HT. Inflammation markers have been associated with the risk of developing HT in normotensives and in hypertensive patients many of these have emerged as potent prognosticators for target organ damage and for future cardiovascular events. Additionally, antihypertensive agents that seem to exhibit a kind of antiinflammatory action and novel agents targeting inflammation have been studied and provide new insights for the treatment of HT. Finally, the article of Bouras et al. [8] is dedicated to the inflammatory mechanisms in CHF and provides an elucidating review of the most potent and novel biomarkers of ongoing inflammatory processes in the setting of CHF. Inflammatory mediators participate in CHF pathophysiology by various ways like exerting direct impact on cardiac myocytes, fibroblasts and β-adrenergic receptors leading to hypertrophy, fibrosis and impaired cardiac contractility, respectively, or inducing apoptosis by stimulation of the proper genes. They utter a brief and essential reference to the anti-inflammatory effects of current CHF therapeutic strategies, while providing an up-to-date and intriguing summary of the most novel and promising antiinflammatory drugs that may gain a place in CHF treatment in the years to come. The purpose of this series of mini-reviews is to highlight the most potent biomarkers of inflammation in pathophysiology of dyslipidemias, HT, AF, ACSs and CHF, clarify their utility as possible indicators of diagnosis and disease progression and present current and promising future therapeutic strategies. We would like to express our sincere thanks to the Editor-in-Chief, Professor Atta-ur-Rahman for giving us the opportunity to contribute to this special issue. Finally, we would like to thank all the authors for their effort and the quality of their work.

Low-grade chronic inflammation is now being held as an important process in the development of atherosclerosis, with new links between dyslipidemia and inflammation being constantly found. While most studies aim to discover inflammatory pathways leading from dyslipidemia to atherogenesis, there is evidence that inflammation can also act in reverse, altering lipid metabolism in unfavorable ways, possibly creating a vicious cycle of inflammationdyslipidemia- inflammation. This is highly relevant for the search of novel therapeutic targets. In this review, after a brief account of the inflammatory mechanisms leading from dyslipidemia to atherogenesis, we focus on what is currently known about the ways inflammation can impair lipid metabolism and whether anti-inflammatory therapies could have a role in dyslipidemia management.

The “holy grail” of modern interventional cardiology is the salvage of viable myocardial tissue in the distribution of an acutely occluded coronary artery. Thrombolysis and percutaneous coronary interventions, provided they can be delivered on time, can interrupt the occlusion and save tissue. At the same time restoring the patency of the coronary vessels and providing the ischemic myocardium with blood can cause additional tissue damage. A key element of ischemic and reperfusion injury and major determinant of the evolution of damage in the injured myocardium is the inflammatory response. The innate immune system initiates and directs this response which is a prerequisite for subsequent healing. The complement cascade is set in motion following the release of subcellular membrane constituents. Endogenous ‘danger’ signals known as danger-associated molecular patterns (DAMPs) released from ischemic and dying cells alert the innate immune system and activate several signal transduction pathways through interactions with the highly conserved Toll like receptors (TLRs). Reactive oxygen species (ROS) generation directly induces pro-inflammatory cascades and triggers formation of the inflammasome. The challenge lies into designing strategies that specifically block the inflammatory cascades responsible for tissue damage without affecting those concerned with tissue healing.

Atrial fibrillation (AF) is the most common chronic arrhythmia and a source of significant morbidity and mortality. Previous studies have identified numerous risk factors for the development of AF, including hypertension, diabetes mellitus and heart failure, which have known pathophysiologic links with inflammatory processes. The importance of inflammation in inducing and perpetuating AF has been highlighted not only by experimental, epidemiological and cohort observational studies, but also by clinical trials providing evidence that inflammatory pathways are involved in AF pathogenesis. Local and systemic measurements of biomarkers and inflammatory mediators, as well as atrial biopsy studies have also given insight as to the purported relationship between this arrhythmia and inflammation. However, the link between inflammation and AF is still poorly defined and several issues remain unresolved. The present review offers an overview of existing evidence supporting the “inflammatory” hypothesis for AF pathophysiology and potential therapeutic means for counteracting this “foul interplay” between arrhythmia and inflammation.

Essential hypertension is a common health disorder with uncertain etiology and unclear pathophysiology. There is evidence that various systems interact in uncertain ways and mechanisms to cause hypertension. It is also well known that inflammation is a key feature in the initiation, progression and clinical implication of several cardiovascular diseases. Recently, it has become evident that the immune system and inflammatory response are also essential in the pathogenesis of hypertension. Many inflammation markers such as CRP, cytokines, and adhesion molecules have been found elevated in hypertensive patients supporting the role of inflammation in the pathogenesis of hypertension. Also, in normotensive individuals, these markers have been associated with the risk of developing hypertension, whereas in hypertensive patients they have been associated with target organ damage as well as with the risk for future cardiovascular events. Thus, understanding the role of inflammation in hypertension provides new insights for novel therapeutic approaches, targeting inflammation for the treatment of hypertension and its complications.

Heart failure (HF) is a complex heterogeneous syndrome with immune, metabolic and neurohumoral mechanisms interacting and leading to gradual heart contractility impairment. From the first study-to correlate inflammation with HF, inflammation biomarkers have been the subject of intense inquiry in patients with various forms of HF. Chronic HF (CHF) is strongly associated with inflammation in terms of pathogenesis, progression, severity and prognosis. Inflammatory mediators participate in CHF pathophysiology in various ways like exerting direct impact on cardiac myocytes, fibroblasts and β-adrenergic receptors leading to hypertrophy, fibrosis and impaired cardiac contractility, respectively, or inducing apoptosis by stimulation of the proper genes. The anti-inflammatory effects of classical heart failure therapeutic strategies such as ACEI and b-blockers are rather conflicting. Whether novel immunomodulating and anti-inflammatory therapeutic approaches should be added to existing therapies in order to ensure additional benefit to HF patients is under investigation. In this review, we summarize the pathophysiological link between inflammatory processes and CHF, focusing on the role of novel and traditional inflammatory biomarkers and highlighting novel anti-inflammatory therapeutic strategies.

Eight new sulfonilamidothienopyrimidinone derivatives (1-8) were synthesized and evaluated for their antiinflammatory activity on the human keratinocyte line NCTC 2544. The potential anti-inflammatory activity of the derivatives (1-8) was evaluated by determining, through Western blot, the expression of cyclooxygenase (COX)-2, inducible NO synthase (iNOS), intercellular adhesion molecule-1 (ICAM-1), and the release of prostaglandins (PG)E2 and interleukin- 8 (IL-8). Moreover, through ELISA assay, the release of monocyte chemoattractant protein-1 (MCP-1), and interleukin- 8 (IL-8) was analyzed. Our results demonstrated that the derivatives 3, 5, 6 and 8 act as excellent inhibitors of inflammatory markers: iNOS, COX-2, ICAM-1, MCP-1, and IL-8. These findings could be useful for the development of new drugs for the treatment of various inflammatory pathologies.

A series of 36 novel substituted quinazolinone derivatives were synthesized and evaluated for their antiinflammatory activity by carrageenan induced paw inflammation model. The ability of these compounds to inhibit cyclooxygenase (COX-1 and 2) enzyme has been determined in-vitro; the results indicated that quinazolinone derivatives were selective towards COX-2 rather than COX-1. Among the quinazolinone derivatives tested, compound 32 showed better inhibition against COX-2 when compared with Celecoxib. Pharmacophore modeling and 3D QSAR studies were performed in order to elucidate structural insights for the anti-inflammatory activity.

Alzheimer's disease (AD) is a progressive brain disorder which occurs due to lower levels of acetylcholine (ACh) neurotransmitters, and results in a gradual decline in memory and other cognitive processes. Acetycholinesterase (AChE) and butyrylcholinesterase (BChE) are considered to be primary regulators of the ACh levels in the brain. Evidence shows that AChE activity decreases in AD, while activity of BChE does not change or even elevate in advanced AD, which suggests a key involvement of BChE in ACh hydrolysis during AD symptoms. Therefore, inhibiting the activity of BChE may be an effective way to control AD associated disorders. In this regard, a series of quinoxaline derivatives 1-17 was synthesized and biologically evaluated against cholinesterases (AChE and BChE) and as well as against α- chymotrypsin and urease. The compounds 1-17 were found to be selective inhibitors for BChE, as no activity was found against other enzymes. Among the series, compounds 6 (IC50 = 7.7 ± 1.0 µM) and 7 (IC50 = 9.7 ± 0.9 µM) were found to be the most active inhibitors against BChE. Their IC50 values are comparable to the standard, galantamine (IC50 = 6.6 ± 0.38 µM). Their considerable BChE inhibitory activity makes them selective candidates for the development of BChE inhibitors. Structure-activity relationship (SAR) of this new class of selective BChE inhibitors has been discussed.

A series of macrocyclic bis-β-lactams has been synthesized in three good yielding steps using a Staudinger [2+2] cycloaddition reaction of ketene derived from phenoxyacetyl chloride as the key step. The reaction provided a diastereomeric mixture of cis-anti-cis (C2-symmetry) and cis-syn-cis (meso) bis-β-lactam grafted macrocycles which were screened for their in vitro antibacterial and antifungal activities against four human pathogenic bacteria and two pathogenic fungi. Compounds 6a and 6b exhibited antibacterial activity at lower concentration against four bacterial pathogens and compounds 10b and 12a showed antifungal activity against two fungal pathogens when compared to reference control.

The interaction between the HIV-1 transactivator protein Tat and RNA response element (TAR) plays a critical role in HIV-1 transcription. Based on the pharmacophore model of reported inhibitors, a series of novel substituted guanidine indole derivatives was designed, synthesized and evaluated for their in vitro HIV-1 and HIV-2 inhibitory activity using the IIIB strain and ROD strain, respectively. Preliminary biological evaluation indicated that three compounds exhibited marked inhibitory activity against HIV-1 IIIB. Quite unexpectedly, compound a-7 was also endowed with the moderate anti-HIV-2 potency (EC50 = 58.14 'M). In addition, preliminary discussion on the activity results and molecular modeling of these new analogues were presented in this manuscript.

A novel series of apigenin derivatives with phloroglucinol or resorcinol as raw materials were synthesized according to Baker-Venaktaraman reaction and their in vitro inhibitory activities on colorectal adenocarcinoma (HT-29) and leucocythemia (HL-60) cell lines were evaluated by the standard methyl thiazole tetrazolium (MTT) method. The results of biological test showed that some of apigenin derivatives possessed stronger anti-cancer activities than apigenin. Compound 6 showed the strongest activity against colorectal adenocarcinoma (HT-29) and leucocythemia (HL-60) cell lines with IC50 valure of 2.03±0.22 µM, 2.25±0.42 µM, it was better than 5-FU (12.92±0.61 µM, 9.56±0.16 µM), which shows a potential compound for colorectal adenocarcinoma and leucocythemia.