Dopaminergic profile of new heterocyclic N-phenylpiperazine derivatives

Dopamine constitutes about 80% of the content of central catecholamines and has a crucial role in the etiology of several neuropsychiatric disorders, including Parkinson's disease, depression and schizophrenia. Several dopaminergic drugs are used to treat these pathologies, but many problems are attributed to these therapies. Within this context, the search for new more efficient dopaminergic agents with less adverse effects represents a vast research field. The aim of the present study was to report the structural design of two N-phenylpiperazine derivatives, compound 4: 1-[1-(4-chlorophenyl)-1H-4-pyrazolylmethyl]-4-phenylhexahydropyrazine and compound 5: 1-[1-(4-chlorophenyl)-1H-1,2,3-triazol-4-ylmethyl]-4-phenylhexahydropyrazine, planned to be dopamine ligands, and their dopaminergic action profile. The two compounds were assayed (dose range of 15-40 mg/kg) in three experimental models: 1) blockade of amphetamine (30 mg/kg, ip)-induced stereotypy in rats; 2) the catalepsy test in mice, and 3) apomorphine (1 mg/kg, ip)-induced hypothermia in mice. Both derivatives induced cataleptic behavior (40 mg/kg, ip) and a hypothermic response (30 mg/kg, ip) which was not prevented by haloperidol (0.5 mg/kg, ip). Compound 5 (30 mg/kg, ip) also presented a synergistic hypothermic effect with apomorphine (1 mg/kg, ip). Only compound 4 (30 mg/kg, ip) significantly blocked the amphetamine-induced stereotypy in rats. The N-phenylpiperazine derivatives 4 and 5 seem to have a peculiar profile of action on dopaminergic functions. On the basis of the results of catalepsy and amphetamine-induced stereotypy, the compounds demonstrated an inhibitory effect on dopaminergic behaviors. However, their hypothermic effect is compatible with the stimulation of dopaminergic function which seems not to be mediated by D2/D3 receptors.

Cytotoxic and DNA-topoisomerase effects of lapachol amine derivatives and interactions with DNA

The cytotoxic activity of amino (3a-e), aza-1-antraquinone (4a-e) lapachol derivatives against Ehrlich carcinoma and human K562 leukemia cells was investigated. Cell viability was determined using MTT assay, after 48 (Ehrlich) or 96 h (K562) of culture, and vincristine (for K562 leukemia) and quercetin (for Ehrlich carcinoma) were used as positive controls. The results showed dose-dependent growth-inhibiting activities and that the amino derivatives were active against the assayed cells, whereas the 4a-e derivatives were not. The allylamine derivative 3a was the most active against Ehrlich carcinoma, with IC50 = 16.94 ± 1.25 µM, and against K562 leukemia, with IC50 = 14.11 ± 1.39 µM. The analogous lawsone derivative, 5a, was also active against Ehrlich carcinoma (IC50 = 23.89 ± 2.3 µM), although the 5d and 5e derivatives showed lower activity. The interaction between 3a-d and calf thymus DNA was investigated by fluorimetric titration and the results showed a hyperchromic effect indicating binding to DNA as presented of ethidium bromide, used as positive control. The inhibitory action on DNA-topoisomerase II-a was also evaluated by a relaxation assay of supercoiled DNA plasmid, and the etoposide (200 µM) was used as positive control. Significant inhibitory activities were observed for 3a-d at 200 µM and a partial inhibitory action was observed for lapachol and methoxylapachol.

Phenylpyrazolone derivatives inhibit gastric emptying in rats by a capsaicin-sensitive afferent pathway

Dipyrone (Dp), 4-aminoantipyrine (AA) and antipyrine (At) administered iv and Dp administered icv delay gastric emptying (GE) in rats. The participation of capsaicin (Cps)-sensitive afferent fibers in this phenomenon was evaluated. Male Wistar rats were pretreated sc with Cps (50 mg/kg) or vehicle between the first and second day of life and both groups were submitted to the eye-wiping test. GE was determined in these animals at the age of 8/9 weeks (weight: 200-300 g). Ten minutes before the study, the animals of both groups were treated iv with Dp, AA or At (240 μmol/kg), or saline; or treated icv with Dp (4 μmol/animal) or saline. GE was determined 10 min after treatment by measuring % gastric retention (GR) of saline labeled with phenol red 10 min after orogastric administration. Percent GR (mean ± SEM, N = 8) in animals pretreated with Cps and treated with Dp, AA or At (35.8 ± 3.2, 35.4 ± 2.2, and 35.6 ± 2%, respectively) did not differ from the GR of saline-treated animals pretreated with vehicle (36.8 ± 2.8%) and was significantly lower than in animals pretreated with vehicle and treated with the drugs (52.1 ± 2.8, 66.2 ± 4, and 55.8 ± 3%, respectively). The effect of icv administration of Dp (N = 6) was not modified by pretreatment with Cps (63.3 ± 5.7%) compared to Dp-treated animals pretreated with vehicle (62.3 ± 2.4%). The results suggest the participation of capsaicin-sensitive afferent fibers in the delayed GE induced by iv administration of Dp, AA and At, but not of icv Dp.

Anti-parasitic action and elimination of intracellular Toxoplasma gondii in the presence of novel thiosemicarbazone and its 4-thiazolidinone derivatives

Toxoplasma, which infects all eukaryotic cells, is considered to be a good system for the study of drug action and of the behavior of infected host cells. In the present study, we asked if thiosemicarbazone derivatives can be effective against tachyzoites and which morphological and ultrastructural features of host cells and parasites are associated with the destruction of Toxoplasma. The compounds were tested in infected Vero cell culture using concentration screens (0.1 to 20 mM). The final concentration of 1 mM was chosen for biological assay. The following results were obtained: 1) These new derivatives decreased T. gondii infection with an in vitro parasite IC50% of 0.2-0.7 mM, without a significant effect on host cells and the more efficient compounds were 2, 3 (thiosemicarbazone derivatives) and 4 (thiazolidinone derivative); 2) The main feature observed during parasite elimination was continuous morphological disorganization of the tachyzoite secretory system, progressive organelle vesiculation, and then complete disruption; 3) Ultrastructural assays also revealed that progressive vesiculation in the cytoplasm of treated parasites did not occur in the host cell; 4) Vesiculation inside the parasite resulted in death, but this feature occurred asynchronously in different intracellular tachyzoites; 5) The death and elimination of T. gondii was associated with features such as apoptosis-like stage, acidification and digestion of parasites into parasitophorous vacuoles. Our results suggest that these new chemical compounds are promising for the elimination of intracellular parasites by mainly affecting tachyzoite development at 1 mM concentration for 24 h of treatment.

Heparan sulphate, its derivatives and analogues share structural characteristics that can be exploited, particularly in inhibiting microbial attachment

Heparan sulphate (HS) and the related polysaccharide, heparin, exhibit conformational and charge arrangement properties, which provide a degree of redundancy allowing several seemingly distinct sequences to exhibit the same activity. This can also be mimicked by other sulphated polysaccharides, both in overall effect and in the details of interactions and structural consequences of interactions with proteins. Together, these provide a source of active compounds suitable for further development as potential drugs. These polysaccharides also possess considerable size, which bestows upon them an additional useful property: the capability of disrupting processes comprising many individual interactions, such as those characterising the attachment of microbial pathogens to host cells. The range of involvement of HS in microbial attachment is reviewed and examples, which include viral, bacterial and parasitic infections and which, in many cases, are now being investigated as potential targets for intervention, are identified.

Impairment of locomotor activity induced by the novelN-acylhydrazone derivatives LASSBio-785 and LASSBio-786 in mice

The N-acylhydrazone (NAH) analogues N-methyl 2-thienylidene 3,4-benzoylhydrazine (LASSBio-785) and N-benzyl 2-thienylidene 3,4-benzoylhydrazine (LASSBio-786) were prepared from 2-thienylidene 3,4-methylenedioxybenzoylhydrazine (LASSBio-294). The ability of LASSBio-785 and LASSBio-786 to decrease central nervous system activity was investigated in male Swiss mice. LASSBio-785 or LASSBio-786 (30 mg/kg, ip) reduced locomotor activity from 209 ± 26 (control) to 140 ± 18 (P < 0.05) or 146 ± 15 crossings/min (P < 0.05), respectively. LASSBio-785 (15 or 30 mg/kg, iv) also reduced locomotor activity from 200 ± 15 to 116 ± 29 (P < 0.05) or 60 ± 16 crossings/min (P < 0.01), respectively. Likewise, LASSBio-786 (15 or 30 mg/kg, iv) reduced locomotor activity from 200 ± 15 to 127 ± 10 (P < 0.01) or 96 ± 14 crossings/min (P < 0.01), respectively. Pretreatment with flumazenil (20 mg/kg,ip) prevented the locomotor impairment induced by NAH analogues (15 mg/kg, iv), providing evidence that the benzodiazepine (BDZ) receptor is involved. This finding was supported by the structural similarity of NAH analogues to midazolam. However, LASSBio-785 showed weak binding to the BDZ receptor. LASSBio-785 or LASSBio-786 (30 mg/kg,ip, n = 10) increased pentobarbital-induced sleeping time from 42 ± 5 (DMSO) to 66 ± 6 (P < 0.05) or 75 ± 4 min (P < 0.05), respectively. The dose required to achieve 50% hypnosis (HD50) following iv injection of LASSBio-785 or LASSBio-786 was 15.8 or 9.5 mg/kg, respectively. These data suggest that both NAH analogues might be useful for the development of new neuroactive drugs for the treatment of insomnia or for use in conjunction with general anesthesia.

Ochratoxin A in Brazilian green coffee

Ochratoxin A is a nephrotoxic, teratogenic and imunotoxic compound produced by Aspergillus and Penicillium spp. It is a suspected carcinogen to humans and it is carcinogenic to rats. Recently it has drawn attention because it has been found in coffee and it has been the object of regulation by coffee importing countries. Brazil is the largest coffee producing country and its largest consumer. In order to conduct an initial assessment of the situation of the coffee produced in the country and offered to its population, one hundred and thirty two samples of Brazilian green coffee from 5 producing states (Minas Gerais, Paraná, São Paulo, Espírito Santo and Bahia) and destined for the home market, were collected at sales points at the cities of Londrina and Santos, Brazil, and analyzed for ochratoxin A. The toxin was isolated in immunoaffinity columns and quantified by HPLC with florescence detection. The limit of detection was 0.7ng/g and the average RSD for duplicates of the samples was 11%. Twenty seven samples were found contaminated with the toxin and the average concentration for the contaminated samples was 7.1ng/g ochratoxin A. Neither the total number of defects nor the number of specific defects according to the Brazilian coffee classification system (black, partly -- black, sour, stinkers-black, stinkers-green, pod beans) showed any relation to the contamination of the samples with ochratoxin A.

Survey on ochratoxin A in Brazilian green coffee destined for exports

The presence of ochratoxin A (OTA) in foods has led some countries to establish regulatory limits. Although coffee is not a major source of OTA in human consumption, the European Community (EC) may establish limits in the near future, with possible economic impact on producing countries. This study measured the OTA content with HPLC in 37 samples of Brazilian green coffee exclusive destined to the export market and also verified a possible relation between coffee defects and OTA content. The results showed an OTA concentration ranging from < 0.16ng/g (detection limit) to 6.24ng/g (average of 3.20ng/g) for 37 samples. Of the five samples observed for defects, toxin content of sound beans ranged from 0.22 to 0.80ng/g (average 0.46ng/g) and of defective beans from 0.42 to 17.46 (average 4.52ng/g). Morphological differences among sound and defective beans showed no susceptibility for mould invasion under optical microscopy observation. One black bean depicted the presence of mould and spores on observation under Scanning Electron Microscope (SEM). According to this investigation, Brazilian green coffee for export complies with most limits in place.

Brazilian roasted coffee oil obtained by mechanical expelling: compositional analysis by GC-MS

A preliminary analysis by GC-MS comparing the mass spectrum of the compounds with the Wiley 275 L mass spectral data base was used to identify the fatty acids and mainly, some volatile compounds responsible for the flavor of the roasted coffee oil. The oil was obtained by mechanical expelling of Brazilian beans (Coffea arabica) roasted at 238ºC for 10 minutes. Different sample preparation methodologies such as headspace, adsorbent suction trapping and esterification were used. It was possible to identify pyrazines, pyridines, furan derivatives and other compounds not reported in the literature.

Evaluation of Brazilian light ketchups II: quantitative descriptive and physicochemical analysis

Samples of ketchup available on the Brazilian market, one traditional (sweetened with sucrose) and three light versions (sweetened with aspartame, acesulfame-K and a blend of cyclamate, saccharin and stevia) were evaluated for their physicochemical characteristics and sensory profile (Quantitative Descriptive Analysis). Four main groups of attributes were generated: appearance, oral texture, aroma and flavor. The samples presented significant differences in all attributes, except for syneresis and overripe tomato flavor. The highest means for sweetener and bitter tastes and aftertastes were observed for the samples sweetened with acesulfame-K and the blend of sweeteners. Although different characteristics were observed among the products evaluated and, despite the differences in the formulations, the light ketchup sweetened with aspartame was the one that presented properties most similar to those of the traditional ketchup.

Quality of propolis commercialized in the informal market

The purpose of this research was to evaluate the quality of propolis produced and commercialized informally in São Paulo State through physicochemical analyses of ethanolic extracts of propolis (EEP). Thus, 40 samples of in nature propolis, provided by beekeepers from 32 towns, were analyzed. The EEP were prepared in a proportion of 30% (w/v), and the physicochemical tests were performed according to the Technical Regulation of Propolis Identity and Quality. The pH of each EEP sample was also evaluated. Regarding the dry extract, it was observed that 80% of the samples meet the minimum requirements established by the Brazilian legislation. With regard to the oxidizing property, 67.5% of EEP were below the maximum time allowed for oxidation. With regard to the solubility in lead acetate, 97.5% of the samples showed positive results, whereas no sample produced a negative result in terms of solubility in sodium hydroxide. Regarding the concentration of flavonoids, 95% of the samples produced results consistent with the minimum value allowed, and regarding the phenolic compounds, all samples were in accordance with the legislation. The EEP pH was slightly acidic. Therefore, it can be concluded that most EEP is consistently in accordance with the Brazilian legislation, which suggests that good quality propolis is produced by those beekeepers.

Characterization of maturity and quality of Brazilian apirenic grapes in the São Francisco river Valley

The objective of this study was to characterize and correlate maturity and quality of the first varieties of Brazilian seedless grapes 'BRS Clara', 'BRS Linda', 'BRS Morena', and 'Advanced Selection 8' compared with the American variety 'Crimson Seedless' in compliance with the Brazilian Normative/2002 and export standards Advanced Selection 8' is dark reddish, has large clusters, and is a very large ellipsoid berry; 'BRS Morena' is black with medium sized clusters and large berry shaped as ellipsoid to globoid; 'BRS Linda' is light green and has large sized clusters; 'Crimson' is pink and has small clusters with berries varying from medium to large sizes and ellipsoid shaped; and 'BRS Clara' is green yellowish has medium sized clusters and small berry of elongated ellipsoid shape. All varieties evaluated meet the standard for domestic market established as berry size minimum diameter 12 mm. 'BRS Clara' does not meet the export requirements of diameter. Berries of the red grapes 'BRS Morena' and 'Crimson Seedless' are firmer. The pH, titratable acidity, and soluble solids meet the official standards. Larger clusters are less acidic and present higher soluble solids/titratable acidity ratios implying that they are the sweetest type when ripe.

Chemical quality parameters and bioactive compound content of brazilian berries

There is a growing consumer demand for higher healthy foods such as berries which are a rich source of phenolic compounds. The current work evaluated blackberry cultivars: Cherokee, Tupy and Xavante; raspberry cultivars: Heritage, Fallgold and Black; and the hybrid Boysenberry. All berries were grown under homogenous subtropical conditions in Brazil. Black raspberry, Cherokee and Tupy blackberry cultivars showed the highest ratio between soluble solid contents and titratable acidity, and Fallgold and Heritage raspberry showed the highest titratable acidity. Total phenolic content ranged from 2.03 to 5.33 g kg–1 fresh weight and total anthocyanin content registered values from 0.41 to 1.81 g kg–1 fresh weight. The most common phenolic acids were gallic, p-coumaric and ellagic, and for anthocyanins: cyanidin-3-glucoside and malvinidin-3-glucoside. Antioxidant capacity ranged from 14.13 to 21.51 mol equivalent trolox kg–1 fresh weight. Black raspberry, all blackberry cultivars and the Boysenberry hybrid are appropriate to be consumed fresh, while Fallgold and Heritage raspberries are recommended to the food industry. Due to their phenolic richness and antioxidant properties, these fruits are of great interest to the fresh fruit market and to pharmaceutical industries. These results could help breeders and growers when planning the cultivar selection according to their foreseeable destination.

From semi-stagnation to growth in a sino-centric market

According to recent available information, the Brazilian economy may be entering a cycle of sustained growth. The dominant current interpretation points to the progresses made in terms of monetary stability, Balance of Payments and structural reforms. Indeed, without monetary stability and the commercial opening of the economy, investments would not be increasing and credit growth would not be helping the emergence of millions of new consumers. But these achievements should be taken as generally conditioning, rather than actually shaping the new picture. Some unexpected (not rarely positive) consequences of overcoming the long enduring semi-stagnation, the emergence of China as a major player, and its consequences on the necessary re-structuring of the Brazilian industry, seem to be decisive in the present day redefinition of the Brazilian GDP growth potential.

Trust and governance of global value chains: The case of a Brazilian beef processor

Purpose - The purpose of this paper is to offer an exploratory case study comparing one Brazilian beef processor's relationships supplying two different distribution channels, an EU importer and an EU retail chain operating in Brazil. Design/methodology/approach - The paper begins with a short review of global value chains and the recent literature on trust. It gives the background to the Brazilian beef chain and presents data obtained through in-depth interviews, annual reports and direct observation with the Brazilian beef processor, the EU importer and the retailer. The interviews were conducted with individual firms, but the analysis places them in a chain context, identifying the links and relationships between the agents of the chains and aiming to describe each distribution channel. Findings - Executive chain governance exercised by the domestic retailer stimulates technical upgrading and transferring of best practices to local. suppliers. Consequently, this kind of relationship results in more trust within the global value chain. Practical implications - There are difficulties and challenges facing this Brazilian beef processor that are party related to the need to comply with increasingly complex and demanding food safety and food quality standards. There is still a gap between practices adopted for the export market and practices adopted locally. The strategies of transnational retailers in offering differentiated beef should be taken in account. Originality/value - The research outlines an interdisciplinary framework able to explain chain relationships and the kind of trust that emerges in relationships between EU importer/retail and a developing country supplier.