Mini Reviews in Medicinal Chemistry - Volume 13, Issue 8, 2013

Since the synthesis of 4,6-dinitrobenzofuroxan in 1899 by Drost, benzofuroxans have attracted particular attention. This peculiar series of compounds exhibit a broad spectrum of biological activity including antibacterial, antifungal, antileukemic, acaricide and immunodepressive properties. These works embrace a period of more than 50 years since the pioneering paper of Gosh and Whitehouse and papers in this major field of the heterocyclic chemistry are still published in 2013. The review has been built in two independent parts. The first one is directly dedicated to the structure of substituted benzofuroxans and will show many medicinal applications of these compounds such as nitric oxide-releasing abilities, induction of oxidative stress, potent anti-cancer agents, anti-chagas agent, target for antiamoebic agent, Ca2+ channel blockers or cytotoxic, mutagenic and genotoxic agent… The second part of this review will be in close connection with the use of benzofuroxans as synthetic precursors in the preparation of new biological compounds such as quinoxaline dioxide, benzimidazole and phenazine derivatives. The interaction of substituted benzofuroxans with electron rich heterocycles or carbanions is the key step in the synthesis of these new biological active compounds. These derivatives can be used as cytotoxic drugs, antimycobacterial agent and display anti-malarial, antileishmanial and antituberculosis activity. The nature of the substituent linked to the carbocyclic ring of benzofuroxan is of primary importance to understand the medicinal properties of this family of compounds. For example, when benzofuroxans are substituted by electron-releasing substituents, the chemical reactivity is transferred from the carbocyclic ring to the furoxan ring.

Several observational and intervention studies have found an inverse association between the risk of cardiovascular disease and the consumption of polyphenol-rich foods and beverages such as cocoa, fruit and vegetables, tea, virgin olive oil and wine. We present here an overview of the latest research on the beneficial effect of dietary polyphenols on blood pressure, focusing on the development of urine biomarkers for an accurate estimation of polyphenol intake. Total polyphenols (TP) excreted in spot urine samples have been successfully used as a biomarker of the consumption, bioavailability and accumulation of TP in a cross-sectional clinical trial. In addition, we describe how the vasoprotective effect of dietary polyphenols has been related to their ability to increase endothelial synthesis of nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF)-mediated responses.

Natural products have been the single most productive source of leads for the development of drugs, because of the great variety of their chemical structures. Previous chemical investigation of members of the genus Cystoseira resulted in the discovery of various bioactive secondary metabolites. The secondary metabolites isolated and characterized are very interesting, both from the biological activity and structural complexity points of view, which make this genus an attractive target for further investigations. The present review covers the research progress on natural products isolated from this genus since January 1995 until now, concerning the isolation and structural elucidation of the secondary metabolites from Cystoseira species. In this contribution significant biological properties are briefly discussed. Simultaneously, we gradually construct an intra-molecular pathway that logically interrelates the isolated compounds.

The research and development of calixarenes, cyclodextrins and fullerenes, which constitute the major classes of supramolecular organic host compounds, have been quite rapidly developing, increasingly active and newly rising highlight interdisciplinary fields. Numerous efforts have been directed toward such molecules as new platforms for anti- HIV drug design. This work briefly reviewed the recent development of calixarenes, cyclodextrins and fullerenes as new chemical entities of distinct anti-HIV activities. It is hoped that this review will serve as a stimulant for new thoughts in the quest for rational designs of more active and less toxic biological molecules as anti-HIV drugs.

Cantharidin (CTD), a natural toxin, can inhibit a variety of tumor cell lines, especially hepatocellular carcinoma cells. It is a strong inhibitor of protein phosphatase type 1 (PP1) and type 2A (PP2A). Because of the cytotoxicity, the clinical application of CDT is limited. Here, we review the structure-activity relationships of CDT analogues, including norcantharidin (NCTD), cantharimides and related derivatives of CTDs, which have more powerful antitumor activity but less cytotoxicity than CDT itself. Important advances in the design of the CTD-based inhibitors achieved recently are outlined here in order to establish principles for synthesis, screening, and the applications of promising anti-cancer drug candidates. In addition, efforts to ameliorate the intrinsic cytotoxicity through the use of drug carriers are also discussed. It is conceivable that rational design of the protein phosphatase inhibitors based on cantharidin analogues can be facilitated by studies of mechanism of the protein-inhibitor interactions and the related structural biology in the future.

4-Aminoquinazoline analogs have been identified as a new class of cancer chemotherapeutic agents with significant therapeutic efficacy against solid tumors. They are potent and highly selective inhibitors of tyrosine kinase (TK) and epidermal growth factor receptor (EGFR). Till date various 4-aminoquinazoline analogs have been synthesized and evaluated for anticancer activity. This review is an attempt to compile the medicinal chemistry of various synthesized 4-aminoquinazoline analogs.

Increased level of serum cholesterol (hyperlipidemia) is the most significant risk factor for the development of atherosclerosis. Cholesterol levels are affected by factors such as rate of endogenous cholesterol synthesis, biliary cholesterol excretion and dietary cholesterol absorption. Acyl CoA: Cholesterol O-acyl transferases (ACAT) are a small family of enzymes that catalyze cholesterol esterification and cholesterol absorption in intestinal mucosal cells and maintain the cholesterol homeostasis in the blood. Inhibition of the ACAT enzymes is one of the attractive targets to treat hyperlipidemia. Literature survey shows that structurally diverse compounds possess ACAT inhibitory properties. In this review, a comprehensive presentation of the literature on diverse ACAT inhibitors has been given.

Over the last few decades, numerous articles dealing with acridine have been reported providing solid background for drug design. Interest in thioacridine/thioacridone derivatives is demonstrated by their use against varied pharmacological activities. The article summarizes the synthetic routes of thioacridine/thioacridone and wide range of their uses including receptor interaction, enzyme inhibition, anti-proliferative effects, anti-microbial activity, etc. The first synthetic route for thioacridone includes the use of acridone with sulfur at high temperature. In order to improve the yield and the laborious reaction conditions other new synthetic methodologies were developed. It has been multi substituted with variety of functional groups which have a substantial impact on their biological activities. The diversity in the biological response has prompted researchers to explore this skeleton to its potential against several activities. Our aim is to review the most promising therapeutic developments dealing with thioacridine/thioacridone derivatives by pinpointing the new trends and the promising therapeutic directions.

Spirulina spp. and its processing products are employed in agriculture, food industry, pharmaceutics, perfumery and medicine. Spirulina has several pharmacological activities such as antimicrobial (including antiviral and antibacterial), anticancer, metalloprotective (prevention of heavy-metal poisoning against Cd, Pb, Fe, Hg), as well as immunostimulant and antioxidant effects due to its rich content of protein, polysaccharide, lipid, essential amino and fatty acids, dietary minerals and vitamins. This article serves as an overview, introducing the basic biochemical composition of this algae and moves to its medical applications. For each application the basic description of disease, mechanism of damage, particular content of Spirulina spp. for treatment, in vivo and/or in vitro usage, factors associated with therapeutic role, problems encountered and advantages are given.