Thiosemicarbazones are a class of compounds of interest for Medicinal Chemistry, as they are structurally diverse and have numerous biological activities reported in the literature. This study describes the synthesis of seventeen thiosemicarbazones, which were investigated as potential therapeutic agents for the treatment of Alzheimer's disease through antioxidant tests and an inhibitory assay of the acetylcholinesterase enzyme. All compounds showed excellent inhibition of acetylcholinesterase and exhibited excellent antioxidant action when compared to the standards. In addition, a quantum study was carried out, in which the HOMO (highest occupied molecular orbital) and LUMO (lowest unoccupied molecular orbital) energy values of each compound were obtained. From these theoretical data, chemical properties were calculated and correlated with the experimental data.

The aim of this research was to evaluate the fractions obtained from the leaf, stem and roots of Allamanda schottii Pohl, Apocynaceae, responsible for the cytotoxicity, using several cell lines. Cytotoxicity was correlated with the season the part of the plant, and the major compounds were assessed. The ethanol extracts of leaves, stems and roots obtained at different seasons were evaluated in the human erythromyeloblastoid leukemia cell line (K562). Subsequently the ethanol extracts and dichloromethane fractions collected in winter were evaluated in mouse fibroblast cell line (Mus musculus) (L929), cervix adenocarcinoma (HeLa), human pre-B leukemia (Nalm6), as well as K562 cell line. The compounds plumericin, plumieride and ursolic acid isolated from ethanol extracts of the stems were evaluated in the same cell lines, as well as on breast adenocarcinoma cell line (MCF-7), and Mus musculus skin melanoma cell line (B16F10). The chromatographic profiles of the dichloromethane fractions were obtained by high performance liquid chromatography. The results revealed that the season during which A. schottii was collected, and the part of the plant analyzed, influence the cytotoxicity on the K562 cells tested. On the other hand the dichloromethane fractions, mainly from the stems and roots, are responsible for the cytoxicity on the cells tested. These results may be associated with the seasonal variation of plumericin in these parts of the plant. This information is in accordance with the HPLC analysis. The results clearly show the potential for the phytotherapeutic use of this species, and suggest that the cytotoxic activity observed may be due to the presence of plumericin, or to minor compounds not yet identified. The seasonal influence on the production of secondary metabolites was verified.

A doença de Chagas, uma infecção parasitária amplamente distribuída na América Latina, é um problema grave de saúde pública com conseqüências devastadoras em termos de morbidade e mortalidade humana. A enzima cruzaína é a principal cisteíno protease do Trypanosoma cruzi, agente etiológico da tripanossomíase Americana ou doença de Chagas, e foi selecionada como alvo atrativo para o desenvolvimento de novos fármacos tripanocidas. No presente trabalho, a síntese e os efeitos inibitórios de uma série de trinta e três chalconas e sete hidrazidas são descritos contra a enzima cruzaína de T.cruzi. A maioria dos compostos mostraram inibição promissora in vitro (valores de IC50 na faixa de 20-60 μM), o que sugere o potencial desses compostos como candidatos a líderes para contínuo desenvolvimento. Doze compostos são inéditos, sendo que quatro destes (7, 13, 16 e 18) estão entre os inibidores mais potentes da série.

Chagas' disease, a parasitic infection widely distributed throughout Latin America, is a major public health problem with devastating consequences in terms of human morbidity and mortality. The enzyme cruzain is the major cysteine protease from Trypanosoma cruzi, the etiologic agent of American trypanosomiasis or Chagas' disease, and has been selected as an attractive target for the development of novel trypanocidal drugs. In the present work, we describe the synthesis and inhibitory effects of a series of thirty-three chalcone and seven hydrazide derivatives against the enzyme cruzain from T. cruzi. Most of the compounds showed promising in vitro inhibition (IC50 values in the range of 20-60 μM), which suggest the potential of these compounds as lead candidates for further development. Twelve compounds have not been reported before, and four of them (7, 13, 16 e 18) are among the most potent inhibitors of the series.

Este trabalho descreve a preparação de ésteres e amidas derivados do ácido caurenóico e a avaliação da atividade antifúngica frente a cepas padronizadas de fungos patogênicos. Ésteres alquílicos e benzílicos foram obtidos com bons rendimentos, sob condições brandas, a partir da esterificação do ácido caurenóico com haletos de alquila em KOH-acetona. Todos os compostos sintetizados foram submetidos aos testes de inibição contra leveduras, hifomicetos e dermatófitos, mas somente o ácido caurenóico e os derivados contendo um grupo carboxilato livre apresentaram atividade moderada frente a dermatófitos.

Representative esters derived from kaurenoic acid were prepared in order to evaluate their antifungal properties. Alkyl and substituted benzyl esters were obtained in good yield under mild conditions by esterification of kaurenoic acid with the corresponding alkyl halide in KOH-acetone. All synthesized compounds were tested for antifungal properties against pathogenic yeasts, hialohyphomycetes and dermatophytes. Kaurenoic acid and derivatives containing a free carboxyl group were moderately active against dermatophytes.

Três triterpenos pentacíclicos inéditos foram isolados da resina de Protium kleinii. Suas estruturas, 3-oxo-11beta,16beta-diidróxi-urs-12-eno (1), 3-oxo-11beta-hidróxi-urs-12-eno (2) e 3-oxo-11beta-hidróxi-olean-12-eno (3), foram elucidadas por espectroscopia de RMN. A administração sistêmica destes compostos (10-100 mg kg-1, i.p.) foi capaz de inibir tanto a primeira quanto a segunda fase da nocicepção induzida pela formalina em camundongos. Em adição, foram isolados os triterpenos conhecidos 3beta,16beta-dihidróxi-urs-12-eno (breina) (4) e uma mistura de alfa (5)- e beta-amirina (6).

Three novel pentacyclic triterpenes have been isolated from the resin of Protium kleinii and their structures elucidated by NMR spectroscopy as 3-oxo-11beta,16beta-dihydroxy-urs-12-ene (1), 3-oxo-11beta-hydroxy-urs-12-ene (2) and 3-oxo-11beta-hydroxy-olean-12-ene (3). The systemic administration of the above compounds (10-100 mg kg-1, i.p.) was able to inhibited both first and second phase of the formalin-induced nociception in mice. The known triterpenes 3beta,16beta-dihydroxy-olean-12-ene (brein) (4) and a mixture of alpha (5)- and beta-amyrin (6) were also found.

O índice semi-empírico topológico, desenvolvido previamente por Heinzen e Yunes, foi aplicado para predizer a retenção cromatográfica de cetonas e aldeídos alifáticos, em fases estacionárias de diferentes polaridades (HP-1, HP-50, DB-210 e Innowax). Foram estabelecidas regressões lineares simples entre os índices de retenção experimentais e os índices semi-empíricos topológicos (RI Exp = a + bI ET) para cada fase estacionária separadamente, sendo que os parâmetros estatísticos obtidos foram de qualidade satisfatória. A polaridade das fases estacionárias indicada pela polaridade de McReynolds (P R), encontra-se refletida nos coeficientes das equações (a e b) obtidos para HP-1, HP-50, DB-210 e Innowax, os quais aumentam linearmente a medida que a polaridade também aumenta (intercepto). As análises estatísticas indicaram que os modelos de correlação quantitativa estrutura-retenção cromatográfica (QSRR) obtidos em fases estacionárias de baixa a média polaridade (HP-1 e HP-50) têm maior estabilidade e habilidade de predição do que os obtidos em fases estacionárias polares (DB-210 e Innowax). Sendo assim, pode-se concluir que, em fases estacionárias consideradas de baixa a média polaridade, o método semi-empírico topológico empregando somente um descritor obteve melhores resultados do que métodos que utilizaram descritores múltiplos.

The semi-empirical topological index, previously developed by Heinzen and Yunes, has been applied to predict the chromatographic retention of aliphatic ketones and aldehydes on stationary phases of different polarities (HP-1, HP-50, DB-210 and Innowax). Simple linear regressions between the retention indices and the semi-empirical topological indices (RI = a + bI ET) were established for each stationary phase separately, showing satisfactory statistical parameters. The polarity of the stationary phases, indicated by McReynolds polarity (P R), is reflected in the coefficients of the equations (a and b) obtained for HP-1, HP-50 and DB-210, which linearly vary as the polarity of the stationary phase increases (intercept). Statistical analyses showed that the quantitative structure-chromatographic retention relationship (QSRR) models obtained on stationary phases of low-to-medium polarity (HP-1 and HP-50) have higher stability and predictive ability than those on polar stationary phases (DB-210 and Innowax). Thus, it can be concluded that the semi-empirical topological method, using only one descriptor, yielded better results on low-to-medium polarity stationary phases than methods that used multiple descriptors.

Cyclic imides consists of an important family of organic compounds with therapeutic potential. In this review, emphasis will be given to the chemical and biological aspects of several sub-classes of this family, incluing maleimides, succinimides, glutarimides, naphtalimides, etc. Additionally, will be focused the contribution of our research group in this field.

We discuss briefly the development and the present status of medicinal chemistry. In this context, we consider the therapeutic possibilities of the phytotherapy. On the basis of this analysis, the development of the phytopharmaceutical industry in Brazil is shown to be of essential importance for both the university and the Country due to the human and technological resources involved.

O estudo de correlação entre estrutura-retenção (QSRR) foi usado para relacionar a retenção cromatográfica de diferentes cumarinas substituídas as suas características estruturais. Diferentes parâmetros estruturais foram selecionados tais como: descritores topológicos, geométricos, eletrônicos, químico-quânticos e físico-químicos para encontrar uma equação que melhor explique o comportamento cromatográfico destes compostos. O método proposto por Dimov que classifica os descritores em diferentes grupos de acordo com seus valores de coeficientes de correlação foi utilizado neste estudo. As melhores equações de correlação linear múltipla foram obtidas com os seguintes descritores: área total (A T), índice do estado eletrotopológico (S-O-) e orbital molecular ocupado de maior energia (E HOMO), mostrando que a retenção experimental, usando fase estacionária de baixa polaridade está relacionada principalmente com fatores relacionados a forma e também eletrônicos. Os modelos selecionados apresentaram uma boa predictabilidade, a qual foi estabelecida através dos valores do coeficiente de correlação de validação cruzada (r²cv). As equações encontradas podem ser utilizadas para auxiliar na elucidação da estrutura ou retenção cromatográfica de cumarinas similares às estudadas.

Quantitative structure-retention relationships (QSRR) were used in this study to relate the chromatographic retention of different substituted coumarins to molecular structure. Different structural parameters were selected, such as topological, geometric, electronic, quantum-chemical and physico-chemical descriptors, in order to find an equation that fitted the chromatographic retention of these compounds. The method proposed by Dimov that classifies the descriptors in different groups in agreement with their values of correlation coefficients was analysed. Significant correlation equations were obtained with the following molecular descriptors: the total surface area (A T), the electrotopological state index (S(-o-)) of the oxygen in position 1 of coumarin, and the highest occupied molecular orbital energy (E HOMO), showing that the experimental retention, using stationary phases with low polarity, was related with the shape and electronic factors of the solutes. The models found have a good predictive ability as established by cross-validation r²cv values and thus, can be used to aid in the elucidation of the structure or the chromatographic retention of similar coumarins.

A estrutura cristalina e cálculos quânticos semi-empíricos de N,N’-(2’-furfurilideno)bis(morfolina), C13H20N2O3, mostram que: i) o valor de 115,1(2)° do ângulo entre o carbono centro da reação e o nitrogênio de uma morfolina; ii) o carbono centro da reação está fora do plano de mínimos quadrados do anel furano, e estes dois fatos explicam a alta instabilidade observada na síntese e conservação do composto. A estrutura cristalina do composto foi determinada por difração de raios-X, no sistema cristalino monoclínico, grupo espacial C2/c (No. 15) e dimensões de cela a = 18,824(4), b = 7,039(1) c = 20,644(4) Å, beta = 97,32(3)°, V = 2713(2) ų, Z = 8, Dcalc = 1,235 Mg m-3, lambda(MoKalfa) = 0,71073 Å, mi = 0,088 mm-1, F(000) = 1088, T = 295 K, R = 4,35% (wR = 13,3%), com 2454 reflexões medidas, 2376 reflexões independentes, 1731 com I > 2sigma(I) e 206 parâmetros refinados. A molécula exibe contatos intramolecular dos tipos C-H...O e C-H...N. O empacotamento molecular envolve contatos intermoleculares do tipo C-H...O.

The crystal structure and semi-empirical quantum chemical calculations of N,N’-(2’-furfurylidene)bis(morpholine), C13H20N2O3, show that: i) the value of 115.1(2)° for the angle between the carbon atom center of the reaction and the nitrogen atom of one morpholine and ii) the carbon atom center of the reaction is outside the least-squares plane of the furan ring, and these two facts explain the high instability observed in the synthesis and conservation of this compound. The crystal structure of the compound was determined via X-ray diffraction in the monoclinic crystal system, space group C2/c (Nr. 15) and cell dimensions a = 18.824(4), b = 7.039(1) c = 20.644(4) Å, beta = 97.32(3)°, V = 2713(2) ų, Z = 8, Dcalc = 1.235 Mg m-3, lambda(MoKalpha) = 0.71073 Å, mu = 0.088 mm-1, F(000) = 1088, T = 295 K, R = 4.35% (wR = 13.3%), with 2454 measured reflections, 2376 independent reflections, 1731 with I > 2sigma(I) and 206 refined parameters. The molecule has C-H...O and C-H...N intramolecular contacts. The molecular packing involves C-H...O intermolecular contacts.

In the present paper we discuss, based in our experience, some experimental procedures which may be employed for isolation of active compounds from medicinal plants. We have also emphasized some insights about the way to obtain more active and selective compounds from natural products through structural modifications oriented for analysis of structure-activity relationships.

Bradykinin (BK) a nonapeptide generated in plasma during tissue injury, is involved in many physiological and pathological states. Kinin actions are mediated by specific membrane receptors and involve a complex signal transducer and also second messager mechanisms. Due to its inequivocal relevance, an intensive effort has been focused in recent years to develop selective and competitive BK antagonists. Thus, the development of a new series of peptide BK antagonists has made an important contribution to the understanding of the pharmacological, physiological and pathophysiological role of BK, and this is certain to provide a firm basis for developing new drugs to relieve pain and inflammation. However, BK antagonists derived from peptide origin reported to date have limited clinical use due to their poor oral absortion and short duration of effect. Thus, considerable effort has also been made in developing stable nonpeptide BK antagonists. Up to now, most nonpeptide compounds reported to exhibit BK antagonistic activity have been derived from plants, including many flavonoids, terpenes, and also synthetic substances with various molecular structures. Amongst them, the pregnane glycoside compounds isolated from the plant Mandevilla velutina are the most promising. These compounds are effective in antognizing BK responses in a variety of preparations, and they also exhibit potent and long-lasting analgesic and anti-inflammatory activities. The exact mechanism underlying their action however, is not yet completely understood.

A Talauma ovata, (Magnoliaceae), planta encontrada na região Sul do Brasil, e conhecida vulgarmente pelo nome de "baguaçu", é recomendada na medicina popular, na forma de chá das folhas, principalmente para o tratamento do diabetes. O presente estudo foi realizado visando analisar, sob os aspectos fitoquímido e farmacológico, a validade do uso medicinal desta planta, como parte de um "screening" mais abrangente. Quimicamente, o extrato de T. ovata é composto de fitoesteróides, saponinas, alcalóides aporfínicos e taninos. No estudo farmacológico não foi constatado a atividade hipoglicemiante do extrato bruto de T. ovato tanto em animais normoglicêmicos, quanto hiperglicêmicos. Além disso, a alta toxicidade observada para esta planta é um inconveniente para seu emprego medicinal peta população.

Talauma ovata (Magnoliaceae) is used for the treatment of diabetes as an infusion prepared from leaves by the population in some parts of Brazil. In the present work this effect was analysed as part of a general screening of the plant. Chemical analysis demonstrated the occurrence of phytosteroids, saponins, alkaloids and tannins in the crude extract. Pharmacological studies failed to demonstrate a hypoglycemic effect of this plant in normoglycemic, hyperglicemic or alloxan-diabetic rats. The low DL50 obtained for this plant strongly suggeste that its consumption by the population may be hazardous.

Foram efetuados estudos químicos e farmacológicos dos extratos brutos hidroalcóolicos obtidos das folhas ou das raízes de E. argentinum ou de frações semi-purificadas desta planta. Os testes químicos revelaram a existência de alcalóides, fitoesteróides, leucoantocianidinas, glicosídeos flavonóides, cumarinas e taninos. A análise farmacológica in vivo demonstrou que o extrato das folhas é menos tóxico que o da raiz. Tanto o extrato bruto como as frações semi-purificadas obtidas das folhas reduziram a locomoção e pressão arterial de rato e potenciaram o sono barbiturico em camundongos. O extrato bruto, principalmente o da raiz, reduziu o edema induzido por carragenina na pata de rato. Testes in vitro demonstraram que o extrato bruto ou as frações semi-purificadas das folhas produziram uma ação semelhante à cocaína avaliada no canal deferente de rato. Além disso, o extrato bruto produziu relaxamento inespecífico no útero de rata e contração do íleo de cobaia. Os resultados obtidos sugerem que esta planta possui constituintes ativos dotados de distintas propriedades farmacológicas, destacando-se o efeito anti-inflamatório, além de uma ação tipo cocaína, merecendo, portanto, estudos químicos e farmacológicos complementares.

Chemical and pharmacological studies were carried out using crude hydroalcholic extracts obtained from the leaves or roots of E. argentinum or the semipurified fractions of this plant. Chemical analysis detected the presence of alkaloids, phytosteroids, leucoanthocianidins, flavonoid glycosides, cumarins and tannins. Qualitatively similar pharmacological effects were observed in experiments using both extracts from the leaves or roots. Experiments in vivo revealed that the crude extract and the semipurified fractions from the leaves reduced locomotor activity, blood pressure, carragenin-induced paw edema and potentiated barbiturate-induced sleeping-time in laboratory animals. In vitro studies demonstrated that the leaf extract or the semipurified fractions induced a cocaine-like effects on the rat vas deferens, a non-specific relaxation of the rat uteri and a contraction of the guinea-pig ileum. It is concluded that E. argentinum contains active compounds responsible for the antiinflammatory effect and cocaine-like action observed in vitro, which merit emphasis in future research.