Current Clinical Pharmacology - Volume 5, Issue 1, 2010

Chalcones (1,3-diaryl-2-propen-1-ones) are open chain flavonoids that are widely biosynthesized in plants. They are important for the pigmentation of flowers and, hence, act as attractants to the pollinators. As flavonoids, chalcones also play an important role in defense against pathogens and insects. A longstanding scientific research has shown that chalcones also display other interesting biological properties such as antioxidant, cytotoxic, anticancer, antimicrobial, antiprotozoal, antiulcer, antihistaminic and anti-inflammatory activities. Some lead compounds with various pharmacological properties have been developed based on the chalcone skeleton. Clinical trials have shown that these compounds reached reasonable plasma concentrations and did not cause toxicity. For these reasons, chalcones became an object of continued interest in both academia and industry. Nowadays, several chalcones are used for treatment of viral disorders, cardiovascular diseases, parasitic infections, pain, gastritis, and stomach cancer, as well as like food additives and cosmetic formulation ingredients. However, much of the pharmacological potential of chalcones is still not utilized. The purpose of this review is to describe the recent efforts of scientists in pharmacological screening of natural and synthetic chalcones, studying the mechanisms of chalcone action and relevant structure-activity relationships. Put together, these activities aimed at synthesis of pharmacologically active chalcones and their analogs.

Homocysteine is a sulfur-containing aminoacid produced during metabolism of methionine. Since 1969 the relationship between altered homocysteine metabolism and both coronary and peripheral atherotrombosis has been known; in recent years experimental evidences have shown that elevated plasma levels of homocysteine are associated with an increased risk of atherosclerosis and cardiovascular ischemic events. Several mechanisms by which elevated homocysteine impairs vascular function have been proposed, including impairment of endothelial function, production of Reactive Oxygen Species (ROS) and consequent oxidation of low-density lipids. Folic acid and B vitamins, required for remethylation of homocysteine to methionine, are the most important dietary determinants of homocysteinemia and daily supplementation typically lowers plasma homocysteine levels. Recently, large-scale intervention trials have been conducted to determine whether lowering homocysteine concentrations through B vitamins supplementation can decrease cardiovascular risk in healthy subjects or improve survival in patients with coronary heart disease. Some of these trials found no significant beneficial effects of combined treatment with folate and vitamin B12, with or without vitamin B6, in spite of adequate homocysteine lowering. In conclusion, it is still unclear whether decreasing plasma levels of homocysteine through diet or drugs may be paralleled by a reduction in cardiovascular risk.

The first step in finding a “drug” is screening chemical compound databases against a protein target. In silico approaches like virtual screening by molecular docking are well established in modern drug discovery. As molecular databases of compounds and target structures are becoming larger and more and more computational screening approaches are available, there is an increased need in compute power and more complex workflows. In this regard, computational Grids are predestined and offer seamless compute and storage capacity. In recent projects related to pharmaceutical research, the high computational and data storage demands of large-scale in silico drug discovery approaches have been addressed by using Grid computing infrastructures, in both; pharmaceutical industry as well as academic research. Grid infrastructures are part of the so-called eScience paradigm, where a digital infrastructure supports collaborative processes by providing relevant resources and tools for data- and compute-intensive applications. Substantial computing resources, large data collections and services for data analysis are shared on the Grid infrastructure and can be mobilized on demand. This review gives an overview on the use of Grid computing for in silico drug discovery and tries to provide a vision of future development of more complex and integrated workflows on Grids, spanning from target identification and target validation via protein-structure and ligand dependent screenings to advanced mining of large scale in silico experiments.

Ocular infections must be treated with active antibiotics which could be administered by different routes: topical, systemic or intravitreal. In the case of endophthalmitis, the most important factor to avoid permanent damage of retina is an early antibiotic onset. Topical application of these drugs would be ineffective in the treatment of endophthalmitis, because of their poor penetration into the ocular globe. Systemic and intravitreal route of administration are the preferred in this setting, although for hydrophilic antibiotics, such as aminoglycosides, beta-lactams and glycopeptides, diffusion from plasma to vitreous cavity is not high enough to assure clinical efficacy. Intravitreal injection should be the favourite route of administration in this case. Ocular penetration of linezolid and fluorquinolones after systemic administration is excellent; hence intravitreal injections for these agents are not needed to achieve therapeutic concentrations at the vitreous cavity.

Diseases caused by parasitic infections are responsible for considerable morbidity and mortality. The progress in the development of vaccines against parasite infections tends to be slow and the epidemiological control of diseases is unsatisfactory. Currently, chemotherapy remains an essential component of clinical management and disease control programs. In the past 20 years, there was a significant increase in our basic knowledge about structure and biochemical functions of parasites. Several studies to identify unique metabolic pathways and key enzymes for parasite survival are in progress, which may support the development of novel target-based drugs. The mitochondrial respiratory chain of parasites typically shows greater diversity compared with host animals; including the electron transport complexes and their related enzymes; tRNA import, as well as the synthesis of fatty acids, pyrimidines and ubiquinones. These unique aspects may represent promising targets for chemotherapy. This review presents a compilation about the knowledge and understanding of the action of therapeutic agents on mitochondria from parasites and their future perspectives.

Hippuric acid has been a major human metabolite for years. However, there is no well-known documented health benefit associated with it except for excretion of environmental-toxic exposures of aromatic compounds such as toluene, or from dietary protein degradation and re-synthesis by intestinal microflora metabolism of quinic acid via the shikimate pathway. Thus hippuric acid can appear in humans as an excretory product from natural or unnatural sources. It has been believed over the years that the major source of urinary hippuric acid levels in humans has come from environmental toxic solvent exposures. However, more recently it was been shown that approximately 1-2 mM hippuric acid is excreted daily in the urine, even in the absence of organic solvent exposure, signalling abundant metabolic dietary sources of hippuric acid are also apparent. One of these has been dietary proteins. The other is from the well-documented presence of quinic acid in healthy colored foodstuffs. Quinic acid is a key metabolite associated with the shikimate pathway existing only in plants, and it is responsible for essental amino acid biosynthesis such as tryptophan, phenylalanine and tyrosine. Here we review the evidence that the human gastrointestinal tract microflora are responsible for quinic acid metabolism not only to hippuric acid, but more importantly to efficacious antioxidant amino acids and vitamins.