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A lot of diseases are characterized by an increased inflammatory response with an exacerbated production of free radicals. The anti-inflammatory effect of different compounds with antioxidant capacity, as polyphenols present in grape is well known. Therefore, the objective is to evaluate the anti-oxidant and anti-inflammatory activity of waste product of wine production.Six different non-toxic-marc-polar extracts from Malbec and Syrah grape varieties were obtained, their total phenol and flavonoid content were evaluated, and their antioxidant and anti-inflammatory activity were determined.High content of total phenols and flavonoids were found mainly in extracts obtained from Syrah (80.51 ± 16.63 g equivalent to gallic acid/100 g and 25.47 ± 3.33 g equivalent to quercetin/100 g). In addition, they had a high antioxidant effect (above 88.5% of ABTS inhibition by Syrah extracts). Finally, all extracts decreased the nitric oxide (NO) production, but this was more accented when extract from Syrah obtained by infusion was used, which decreased NO levels to baseline (4.46 µM).Taking together, our results show the potential pharmaceutical use of waste product of wine making to prevent or to treat diseases which inflammatory response is exacerbated.

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The full conformational space of N-acetyl-l-cysteine-N-methylamide was explored by ab initio (RHF/ 6-31G(d)) and DFT (B3LYP/6-31G(d)) computations. Multidimensional conformational analysis predicts 81 structures in N-acetyl-l-cysteine-N-methylamide, but only 47 relaxed structures were previously determined at the RHF/3-21G level of theory. These structures were now optimized using RHF/6-31G(d) and B3LYP/6-31G(d) approaches. Seven conformational migrations were observed when recalculated at higher level of theory. Besides these major changes, only smaller conformational shifts were operative for the remaining stationary points. The exploration of the whole conformational space of N-acetyl-l-cysteine-N-methylamide, including the transition-state structures allowing the conformational interconversion among the low-energy forms, was analyzed in this study. Our results offer new insights into the influence of polar side chains on the conformational preferences of peptide structures.

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The antimicrobial activity of Berberis heterophylla leaves, stems and root aqueous extracts was studied in vitro on Gram-positive and Gram-negative bacteria and fungi. The in vitro antifungal activity of berberine isolated from the same source against different Candida species was also investigated.

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Here we report the synthesis, in vitro antifungal evaluation and SAR study of 41 chalcones and analogues. In addition, all active structures were tested for their capacity of inhibiting Saccharomyces cerevisiae beta(1,3)-glucan synthase and chitin synthase, enzymes that catalyze the synthesis of the major polymers of the fungal cell wall.

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As part of our project devoted to the search for antifungal agents, which act via a selective mode of action, we synthesized a series of new 4-aryl- or 4-alkyl-N-arylamine-1-butenes and transformed some of them into 2-substituted 4-methyl-tetrahydroquinolines and quinolines by using a novel three-step synthesis. Results obtained in agar dilution assays have shown that 4-aryl homoallylamines not possessing halogen in their structures, tetrahydroquinolines and quinolines, display a range of antifungal properties in particular against Epidermophyton floccosum and Microsporum canis. Regarding the mode of action, all active compounds showed in vitro inhibitory activities against beta(1-3) glucan-synthase and mainly against chitin-synthase. These enzymes catalyze the synthesis of beta(1-3) glucan and chitin, respectively, major polymers of the fungal cell wall. Since fungal but not mammalian cells are encased in a cell wall, its inhibition may represent a useful mode of action for these antifungal compounds.

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A structure-antifeedant activity relationship (SAR) study of clerodane diterpenoids was carried out. Attention was focused on the feeding-deterrent activities exhibited toward Tenebrio molitor by clerodane diterpenoids and withanolides. Azadirachtin was chosen as a reference compound. SAR studies on the clerodane compounds indicate that the stereoelectronic factors are more important than the hydrophobic aspects as determinants of antifeedant activity. A furan ring in the side chain and a carbonyl alpha,beta-unsaturated (or spiro-epoxide) group appear to be indispensable for the biological response. A conformational study indicate that the optimum interatomic distance between these moieties is a range between 9.5 and 10.5 A. In addition, a similar stereoelectronic response was found among withanolides and azadirachtin. On the basis of these results it is reasonable to imagine a closely related chemical mechanism for these compounds.

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Thirty-four arylpropanoids and related compounds were evaluated in vitro for antifungal properties. Among them, 22 phenyl-, 4 naphthyl-, and 4 phenanthrylpropanoids; naphthalene; phenanthrene; and 2-chloro-1-hexyl-1-propanone were tested against dermatophytes by the agar dilution method. alpha-Halopropiophenones exhibited a broad spectrum of activities against Microsporum canis, Microsporum gypseum, Trichophyton mentagrophytes, Trichophyton rubrum, and Epidermophyton floccosum, with MIC values between 0.5 and >50 microg/mL. Keto, alcohol, and alpha-haloketo propyl derivatives of naphthalene and phenanthrene also showed very good activity against all dermatophytes tested, clearly showing that in these series, a halogen atom is not necessary for activity. Phenanthryl derivatives were more active (MICs, 3-20 microg/mL) than naphthyl ones (MICs, 3-50 microg/mL). A structure-activity relationship study was carried out and aided in establishing the structural requirements of arylpropanoids for antifungal activities. Because dermatophytes are a group of fungi that characteristically infect the keratinized areas of the body, these new series of antifungal compounds open the possibility of discovering new topical antifungal drugs for the treatment of dermatomycoses, which are frequently very difficult to eradicate.

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Acid-base equilibria in ethanol-aqueous solution of 5-acetamido-1,3,4-thiadiazole-2-sulfonamide (acetazolamide, H(2)acm), 5-tertbutyloxycarbonylamido-1,3,4-thiadiazole-2-sulfonamide (B-H(2)ats), 5-amino-1,3,4-thiadiazole-2-sulfonamide (Hats) and 5-amino-1,3,4-thiadiazole-2-thiol (Hatm) at 25 degrees C, 0.15 mol dm(-3) ionic strength (NaNO(3)), have been investigated by potentiometry and UV spectrophotometry. The ionization constants were calculated with SUPERQUAD program from potentiometric measurements and by a method according to Edsall et al. using the mole fractions determined by complementary tri-stimulus colorimetry (CTS). The constants obtained by potentiometry were: B-H(2)ats, pk(a(1))=7.33(3) and pk(a(2))=9.27(1); Hats, pk(a(1))=2.51(3) and pk(a(2))=8.49(1); Hatm, pk(a(1))=1.92(1) and pk(a(2))=6.81(1); whereas the constants determined by spectrophotometry were: H(2)acm, pk(a(1))=7.78(1) and pk(a(2))=9.57(2); B-H(2)ats, pk(a(1))=7.71(2) and pk(a(2))=9.61(2); Hats, pk(a(1))=2.19(3) and pk(a(2))=8.61(2); Hatm, pk(a(2))=6.90(2). Theoretical calculations using MO semiempirical and ab-initio RHF/6-31G* computations for the compounds were also performed. It was possible to clarify the preferred deprotonation mechanism of acetazolamide and B-H(2)ats in which the first deprotonation takes place at the carbonamido group.

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In previous reports we attributed the cytoprotective activity of several sesquiterpene lactones to the presence of a nonhindered electrophilic acceptor in their structure. We suggested that the mechanism of protection would be, at least in part, mediated through a reaction between the electrophilic acceptor and the sulfhydryl-containing groups of the mucosa. We report here the gastric cytoprotective effect of simple molecules containing an alpha, beta-unsaturated carbonyl group. In the present paper, we undertake the study of molecular accessibility and molecular shape, in addition to conformational, electronic, and steric factors. Our results helped to establish two important facts connecting chemical structure with cytoprotective effect. Firstly, an adequate molecular accessibility appears to be necessary to produce the biological response, and secondly, the alpha,beta-unsaturated carbonyl system has to be included in a cyclic structure or, at least, in the proximity of a cyclic system.

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Our previous reports indicate that the cytoprotective effect of helenalin and several sesquiterpene lactones is mediated through a Michael reaction between the sulfhydryl containing peptides of the gastric mucosa and Michael acceptors present in the sesquiterpene lactone molecules. In the present work the different alternative active sites in molecules containing up to three places which could act as viable Michael acceptors are evaluated. To do this, an extensive conformational and electronic study of helenalin and its derivatives was carried out. The experimental and theoretical results obtained show the gamma-lactone and cyclopentenone groups to be the biologically active places of the molecules under study, whereas tiglic and angelic substituents in these compounds show different behavior as Michael acceptors.

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The structural requirements for the gastric cytoprotective activity of several sesquiterpene lactones are reported. A theoretical-experimental study on the potentially active centers is carried out. The biological evaluation of reduced analogues and the simulation of the molecular interactions between these compounds and an endogenous cysteine residue suggest that the presence of a non sterically hindered Michael acceptor seems to be an essential structural requirement for the cytoprotective activity in this family of compounds. This observation suggests that cytoprotection is mediated through a Michael reaction between the sulfhydryl-containing peptides of the mucosa and Michael acceptors present in the molecules under study. This mechanism of action is in addition to and distinct from the one proposed in our previous paper, namely, that these sesquiterpenes stimulate endogenous synthesis of prostaglandins.

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A conformational study of two potent histamine H2-receptor antagonists, tiotidine and nizatidine, have been made. The geometry of cyanoguanidine and guanidinothiazol in tiotidine and diaminonitroetane in nizatidine was obtained using MNDO calculations. On the other hand, the conformations of the molecules, under study were obtained using a empirical atom-atom potential that stimulates the drug behavior in aqueous solution at 37 degrees C. For both molecules, folded and very rigid conformations, with a substantial parallelism between the planes of the rings and the polar groups, were obtained. All the possibilities of the configurational isomerism on the polar groups of this molecules was taken into account. The results obtained show that the polar group can adopt just staggered forms (Z,E and E,Z). These results agree with experimental and theoretical studies made on the polar group. The type of conformations found in tiotidine and nizatidine are very similar to those previously found for metiamide, cimetidine, ranitidine and etintidine. These results would permit us to propose that these conformations play a determinant role in the histamine H2-receptor recognition.

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We describe an electronic and conformational study of histamine H2-receptor ligands of the imidazole series, in which the possibilities of configurational isomerism (the thiourea group) and N3H and N1H tautomerism (imidazole ring) were considered. The results suggest that the conformational flexibility of the molecules and the properties of the imidazole ring are of special importance in the display of H2-receptor activity. A theoretical model of histamine H2-receptor interactions is proposed on the basis of these and other results. A very important characteristic of our model is its ability to explain H2-receptor activation by compounds which differ structurally, and to explain antagonism at the same receptor. The stereospecificity of rigid analogues of cimetidine and tiotidine, and the importance of chain length in flexible histamine H2-antagonists are also accounted for.

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Se realizó un estudio conformacional de dos potentes antagonistas en los receptores de H2 de histamina, tiodidina y nizatidina. Las geometrías de los grupos cianoguanidina y guanidinotiazol de tiotidina y el grupo diaminonitroetano de nizatidina fueron calculadas utilizando técnicas MNDO de la química cuántica. Mientras que las conformaciones de las moléculas en estudio se obtuvieron empleando un potencial átomo-átomo empírico que simula el comportamiento de las drogas en solución acuosa a 37-C. Para ambas moléculas se obtuvieron conformaciones plegadas, muy rígidas con un marcado paralelismo entre el plano de los anillos y el de los grupos polares. En las dos moleculas en estudio todas las posibilidades de isomerismo configuracional de los grupos polares fueron tenidas en cuenta: encontrándose que las únicas conformaciones posible son aquellas que tienen los grupos polares en la forma de los isómeros cruzados (Z-E o E-Z). Estos resultados están totalmente de acuerdo con los estudios experimentales y teóricos realizados en estos grupos polares. El tipo de conformaciones encontradas por totidina y nizatidina son muy similares a las encontradas previamente para metiamida, cimetidina, ranitidina y etintidina. Estos resultados nos permitirían proponer que este tipo de conformaciones juegan un rol determinante en el reconocimiento del receptor H2 de histamina

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