Publications

Abstract Chromones are heterocyclic compounds of natural or synthetic origin that possess relevant pharmacological activities. Versatile functionalization of the chromone nucleus allows attaining of a chemical diversity suitable to perform structure-activity relationships in drug discovery and development programs. Accordingly, the synthesis and identification of novel chromone carboxamide derivatives with electron-donating and electron-withdrawing substituents in different positions of the exocyclic ring are reported in this work. Their complete structural characterization was performed using one-dimensional and two-dimensional resonance techniques. The data acquired are useful for a prompt analysis of related compounds that encompass our integrated medicinal chemistry sketch. Copyright (C) 2013 John Wiley & Sons, Ltd.

Abstract Phenolic acids are ubiquitous antioxidants accounting for approximately one third of the phenolic compounds in our diet. Their importance was supported by epidemiological studies that suggest an inverse relationship between dietary intake of phenolic antioxidants and the occurrence of diseases, such as cancer and neurodegenerative disorders. However, until now, most of natural antioxidants have limited therapeutic success a fact that could be related with their limited distribution throughout the body and with the inherent difficulties to attain the target sites. The development of phenolic antioxidants based on a hybrid concept and structurally based on natural hydroxybenzoic (gallic acid) and hydroxycinnamic (caffeic acid) scaffolds seems to be a suitable solution to surpass the mentioned drawbacks. Galloyl cinnamic hybrids were synthesized and their antioxidant activity as well as partition coefficients and redox potentials evaluated. The structure property activity relationship (SPAR) study revealed the existence of a correlation between the redox potentials and antioxidant activity. The galloyl cinnamic acid hybrid stands out as the best antioxidant supplementing the effect of a blend of gallic acid plus caffeic acid endorsing the hypothesis that the whole is greater than the sum of the parts. In addition, some hybrid compounds possess an appropriate lipophilicity allowing their application as chain-breaking antioxidant in biomembranes or other type of lipidic systems. Their predicted ADME properties are also in accordance with the general requirements for drug-like compounds. Accordingly, these phenolic hybrids can be seen as potential antioxidants for tackling the oxidative status linked to the neurodegenerative, inflammatory or cancer processes.

Abstract ObjectivesIn the present communication, we report the synthesis, pharmacological evaluation, theoretical evaluation of absorption, distribution, metabolism and excretion properties and structure-activity relationship study of a selected series of 3-arylcoumarins (compounds 1-9). Adenosine receptors (ARs) binding activity and selectivity of the synthesized compounds 1-9 were evaluated in this study. Different substituents were introduced in both benzene rings of the evaluated scaffold, at positions 6 and 3 or 4 of the moiety. The lack of data on the 3-arylcoumarin scaffold encouraged us to explore the ARs' binding activity of a selected series of derivatives. MethodsA new series of coumarins (compounds 1-9) were synthesized and evaluated by radioligand binding studies towards ARs. Key findingsAnalysing the experimental data, it can be observed that neither the simple 3-arylcoumarin nor the 4-nitro derivatives presented detectable binding affinity for the evaluated receptors, although most of the other substituted derivatives have good binding affinity profiles, especially against the hA(1)/hA(3) or only hA(3) AR. ConclusionsThe most remarkable derivative is compound 2, presenting the best affinity for hA(3) AR (K-i=2680 nM) and significant selectivity for this subtype.

Abstract The therapeutic potential of natural phenolic antioxidants in human diseases associated with oxidative damage has received great attention to date. Appraisal of literature evidences that, in general, antioxidant therapy has enjoyed relative successes in preclinical studies but little benefits in human intervention studies or clinical trials. In fact, despite the huge, largely untapped potential therapeutic benefit of natural phenolic antioxidants, such as vitamins, non-flavonoid and flavonoid compounds, they appear not to be suitable drug candidates. The problem may be related, among others, to their non-drug-likeness properties. Though controversial the results obtained so far confirm the importance of exploring phenolic natural systems as safe templates for the design of new antioxidants. To support the assumption an outlook of the lead structural optimization process to improve ADME properties was given by means of natural hydroxycinnamic acids as a case study. The optimization of drug physicochemical properties and the development of appropriate delivery antioxidant systems can provide in the next future a way out to attain effective therapeutic antioxidant agents.

Abstract Hydroxycinnamic acids (such as ferulic, caffeic, sinapic, and p-coumaric acids) are a group of compounds highly abundant in food that may account for about one-third of the phenolic compounds in our diet. Hydroxycinnamic acids have gained an increasing interest in health because they are known to be potent antioxidants. These compounds have been described as chain-breaking antioxidants acting through radical scavenging activity, that is related to their hydrogen or electron donating capacity and to the ability to delocalize/stabilize the resulting phenoxyl radical within their structure. The free radical scavenger ability of antioxidants can be predicted from standard one-electron potentials. Thus, voltammetric methods have often been applied to characterize a diversity of natural and synthetic antioxidants essentially to get an insight into their mechanism and also as an important tool for the rational design of new and potent antioxidants. The structure-property-activity relationships (SPARs) correlations already established for this type of compounds suggest that redox potentials could be considered a good measure of antioxidant activity and an accurate guideline on the drug discovery and development process. Due to its magnitude in the antioxidant field, the electrochemistry of hydroxycinnamic acid-based antioxidants is reviewed highlighting the structure-property-activity relationships (SPARs) obtained so far.

Abstract 4-Oxo-N-phenyl-4H-chromene-2-carboxamide, C16H11NO3, crystallizes in the space group P2(1)/n and its derivative 7-methoxy-4-oxo-N-p-tolyl-4H-chromene-2-carboxamide, C18H15NO4, forms two polymorphs which crystallize in the space groups P2(1)/c and P (1) over bar. The structures have an anti-rotamer conformation about the C-N bond; however, the amide O atom can be either trans-or cis-related to the O atom of the pyran ring. The latter compound also crystallizes as a hemihydrate, C18H15NO4 center dot 0.5H(2)O, in the space group C2/c. This compound has a similar structure to that of the unsolvated compound.

Abstract The antioxidant responses of Solanum nigrum L. cell suspension cultures to metalaxyl exposure were investigated. An increase in lipid peroxidation and hydrogen peroxide content, for both concentrations tested (20 mg L-1; 40 mg L-1) revealed the response of oxidative metabolism of cell suspensions to metalaxyl. Superoxide dismutase (SOD; EC 1.15.1.1), catalase (CAT; EC 1.11.1.6) and ascorbate peroxidase (APX; EC 1.11.1.11) activities increased, particularly in the highest concentration of metalaxyl used. An analysis by non-denaturing polyacrylamide gel (PAGE) followed by staining for enzyme activity, revealed seven SOD isoenzymes, two CAT isoenzymes, and nine APX isoenzymes. Metalaxyl levels were quantified in the culture medium and results suggest that suspension cells were able to accumulate and/or degrade the fungicide five hours after exposure. SOD, CAT and APX isoenzymes were differently affected by the metalaxyl treatment. Results suggest that the higher concentration of metalaxyl induced oxidative stress to cell suspension cultures of S. nigrum.

Abstract Both experimental and theoretical methodologies were employed in order to study the possibility of excited state oxyluciferin being formed as the result of the decomposition of a neutral dioxetanone. Excitation measurements in water (at different pH values) and in methanol, along with computational calculations, demonstrated that the hydroxyl-benzothiazole group of firefly dioxetanone and six oxyluciferin analogues is only deprotonated in conditions not in line with the firefly bioluminescence reaction. Thus, a new mechanism involving a neutral firefly dioxetanone must be presented in order to explain the chemiexcitation of oxyluciferin. It was also studied for the first time the interaction between a molecule involved in the bioluminescence reaction (neutral firefly dioxetanone) and the real second conformation of firefly luciferase.

Abstract Phenolic compounds constitute a diverse group of secondary metabolites which are present in both grapes and wine. The phenolic content and composition of grape processed products (wine) are greatly influenced by the technological practice to which grapes are exposed. During the handling and maturation of the grapes several chemical changes may occur with the appearance of new compounds and/or disappearance of others, and consequent modification of the characteristic ratios of the total phenolic content as well as of their qualitative and quantitative profile. The non-volatile phenolic qualitative composition of grapes and wines, the biosynthetic relationships between these compounds, and the most relevant chemical changes occurring during processing and storage will be highlighted in this review. © 2013.

Abstract In this work the synthesis of a new chromone (6-bromo-N-(cyclohex-1-en-1-ylmethyl)-4-oxo-4H-chromene-2-carboxamide) by a strategy performed in three steps is reported. The compound was characterized by NMR (H-1 and C-13) and EIMS and the structure was confirmed by single-crystal X-ray diffraction. The analysis of the X-ray determined that the molecule is built up from two rings, a chromone ring and a cyclohexene ring united by an amide spacer. This new chromone will be valuable for obtaining evidence about the importance of the exocyclic double bound on monoaminoxidase-B (MAO-B) inhibitory activity. (c) 2013 Published by Elsevier B.V.