A complete and unambiguous assignment of 1H and 13C nuclear magnetic resonance (NMR) signals of 29 naphthoquinones is reported on the basis of one- and two-dimensional NMR techniques (1H, 13C, 1H-1H correlated spectroscopy (COSY) and 1H-13C heteronuclear multiple-bond correlation (HMBC)). This is the first report distinguishing data between para-naphthoquinones, ortho- and para-furanonaphthoquinones isomers.

Poincianella pluviosa is a tree whose stem bark is reputed to have antidiarrheal, wound healing, antitumoral and antimalarial properties. Considering that the leaves of the tree are a more abundant and renewable source than the stem bark, we chose to study the antimalarial potential of this organ part. The aqueous leaf extract exhibited a rich phenolic profile. It was active (IC50= 6.88 ± 1.64 µg mL-1) against chloroquine resistant Plasmodium falciparum (W2) without toxicity to HepG2 A16 cells. The organic fraction was more active (IC50= 1.83 µg mL-1) than the aqueous leaf extract itself. Ten phenolic compounds were obtained from the latter. This is the first report on the phenolic composition of P. pluviosa leaves. Ellagic acid (IC50= 0.215 ± 0.007 µg mL-1) proved to be 32 fold more active than the aqueous leaf extract itself. Considering their renewable aspect, leaves of P. pluviosa appear to be a more interesting source of antimalarial compounds than stem bark.

Lupeol, a triterpene frequently found in Asteraceae plant species, showed moderate to low activity in different strains of Plasmodium falciparum, the most virulent malaria etiological agents. In this work, lupeol was isolated from Parahancornia fasciculata, a plant that is used to treat malaria in the Amazonia region. In the search of more activity lupeol derivatives, five new 1,2,3-triazole hybrid molecules were synthetized by copper-catalyzed azide-alkyne cycloaddition. The antiplasmodial activity of the semi-synthetic compounds were evaluated by the lactate dehydrogenase assay; the lupeol propargyl ether was the only one to disclosing increased activity (half maximal inhibitory concentration-IC50-62.0 ± 1.92 µmol L-1) in relation to lupeol (IC50 117.00 µmol L-1). Therefore, this work revealed a new class of interesting lupeol derivatives that can be obtained by linking electron donors to the hydroxy group at C-3.

We herein report the synthesis of hybrid kauranoid molecules of type 1,2,3-triazole-1,4-disubstituted aiming to improve the antimalarial activity of kaurenoic and xylopic acids. The CuI-catalyzed cycloaddition of azides and kauranoid terminal alkynes was explored as a hybridization strategy. Kauranoid terminal alkynes were prepared from kaurenoic and xylopic acids that were isolated from Wedelia paludosa D. C. (Asteraceae) and Xylopia frutescens Aubl. (Annonaceae). A total of 15 kauranoid derivatives, including nine new triazoles, were obtained and five out of these were more active than the original diterpenes. Interestingly, an increased activity was observed for a kauranoid propargyl ether. Interaction between ent-kaurane diterpene derivatives and Ca2+-ATPase (PfATP6) was investigated. Synthesis of diterpene derivatives emerges as a possible route to be explored in the quest of potentially new inhibitors of PfATP6.

Transformações químicas realizadas em eremantolida C (1), uma lactona sesquiterpênica isolada de Lychnophora trichocarpha Spreng. originaram cinco novos derivados: 1′,2′-epoxieremantolida C (2), 5-n-propilamino-4,5-diidro-1′,2′-epoxieremantolida C (3), cloreto de 5-n-propilamônio-4,5-diidro-1′, 2′-epoxieremantolida C (4), cloreto de 5-n-propilamônio-4,5-diidroeremantolida C (5) e 16-O-etileremantolida C (6). As estruturas químicas de todos estes derivados foram elucidadas com base nos espectros de IV, EM, RMN de 1H e de 13C e por meio de técnicas 1D e 2D. Eremantolida C e os derivados 2, 4 e 5 foram avaliados frente a cepas tripomastigotas Y e CL de Trypanosoma cruzi. Eremantolida C inibiu completamente o crescimento de ambas as cepas de parasitas, enquanto todos os derivados foram parcialmente ativos contra a cepa CL e inativos contra a cepa Y.

Chemical transformations of eremantholide C (1), a sesquiterpene lactone that was isolated from Lychnophora trichocarpha Spreng. led to five new derivatives: 1′,2′- epoxyeremantholide C (2), 5-n-propylamine-4,5-dihydro-1′,2′-epoxyeremantholide C (3), 5-n-propylammonium-4,5-dihydro-1′,2′-epoxyeremantholide C chloride (4), 5-n-propylammonium-4,5-dihydroeremantolide C chloride (5) and 16-O-ethyleremantholide C (6). The structures of all these derivatives were assigned on the basis of IR, MS, 1H and 13C NMR data by 1D and 2D techniques. Eremantholide C and the derivatives 2, 4 and 5 were evaluated against trypomastigotes Y and CL strains of Trypanosoma cruzi. Eremantholide C completely inhibited the growth of both the parasites strains while all derivatives were partially active against the CL strain and inactive against the Y strain.

Pectolinarina, uma flavona heterosídica, foi isolada do extrato etanólico das folhas de Distictella elongata (Vahl) Urb., além de uma mistura de ácidos ursólico, pomólico e oleanólico, além de β-sitosterol. Suas estruturas foram estabelecidas com base em análise espectral (RMN de 1H e 13C 1D e 2D) em comparação com a literatura. Esta é a primeira vez em que se relata a ocorrência deste flavonoide em uma espécies da família Bignoniaceae.

Pectolinarin, a flavone heteroside, was isolated from Distictella elongata (Vahl) Urb. leaves ethanol extract, along with a mixture of ursolic, pomolic and oleanolic acids, besides β-sitosterol. Their structures were established on the basis of spectral analysis (1H and 13C NMR, 1D and 2D) and they were compared with literature. This is the first report on the occurrence of this flavonoid in a species of the Bignoniaceae family.

Uma recente reinvestigação das partes aéreas de Wedelia paludosa D.C. é descrita e relata, pela primeira vez, o isolamento do ácido iso-caurenóico desta espécie.

A recent reinvestigation of aerial parts of Wedelia paludosa D.C. is described and reports, for the first time, the isolation of iso-kaurenoic acid from this species.

Maytenus ilicifolia Mart. ex Reissek é tradicionalmente usada no Brasil para o tratamento de úlcera gástrica. O presente trabalho relata a investigação fitoquímica de um extrato etanólico de folhas de M. ilicifolia (EEMIL) visando o isolamento de constituintes que foram usados como marcadores químicos para monitorar o fracionamento de um extrato aquoso liofilizado de folhas de M. ilicifolia (LAEMIL). De EEMIL, quatro flavonóides foram isolados, compreendendo o triglicosídeo flavônico mauritianina (1), trifolina (2), hyperina (4), e epi-catequina (5). O fracionamento de LAEMIL levou a 5 frações, fornecendo um derivado tetraglicosilado de canferol (3), além do galactitol (6). LAEMIL e suas frações foram avaliadas quanto aos efeitos sobre o volume e pH da secreção gástrica em ratos. Análise por CLAE (Cromatografia Líquida de Alta Eficiência) revelou que somente frações contendo o tri- e tetra-glicosídeos flavônicos 1 e 3 causaram aumento significativo de volume gástrico e pH, indicando que esses glicosídeos têm importante papel sob o efeito gastroprotetor de folhas de M. ilicifolia.

Maytenus ilicifolia Mart. ex Reissek is traditionally used in Brazil for treatment of gastric ulcers. Here we report the phytochemical investigation of an ethanol extract of M. ilicifolia leaves (EEMIL) aiming at the isolation of constituents which were used as chemical markers to monitor an activity-guided fractionation of a lyophilized aqueous extract of M. ilicifolia leaves (LAEMIL). From EEMIL, four flavonoids were isolated, namely the tri-flavonoid glycosides mauritianin (1), trifolin, (2) hyperin (4), and epi-catechin (5). Fractionation of LAEMIL led to 5 fractions which afforded the tetra-glycoside kaempferol derivative (3), and galactitol (6). LAEMIL and its fractions were evaluated in rats for their effects on gastric secretion volume and pH. HPLC (High Performance Liquid Chromatography) analysis revealed that only fractions containing the tri- and tetra-flavonoid glycosides 1 and 3 caused significant increase of gastric volume and pH, thus indicating that these glycosides play an important role on the gastroprotective effect of M.ilicifolia leaves.

A malária ainda é um dos mais sérios problemas de saúde pública e a principal causa de mortalidade e morbidade nas regiões endêmicas. O Brasil está entre os 30 países com maior incidência de malária e a maior parte dos casos ocorre na Amazônia Legal. Novos agentes terapêuticos são necessários para o tratamento da malária. Muitas espécies vegetais são utilizadas na medicina tradicional de vários países endêmicos mas é relativamente reduzido o número daquelas que já foram investigadas quanto à sua atividade antimalárica. Menor ainda é o número de espécies das quais foram isoladas substâncias ativas e tiveram sua toxidade determinada. Esta área de pesquisa é, portanto, de alta relevância. Um projeto de descoberta de produtos naturais antimaláricos a partir de plantas de uso tradicional deve incluir ensaios in vitro e in vivo bem como o isolamento biomonitorado de substâncias ativas. Os produtos finais serão substâncias naturais antimaláricas, potenciais fármacos ou protótipos para o desenvolvimento de novos fármacos, e/ou extratos padronizados, com atividade antimalárica, os quais são necessários para estudos pré-clínicos e clínicos quando o objetivo é o desenvolvimento de fitoterápicos (fitomedicamentos) eficazes e seguros. A presente revisão discute estas duas abordagens, apresenta resumidamente as metodologias de bioensaios para avaliação de atividade antimalárica e focaliza a atividade de alcalóides pertencentes a diferentes classes estruturais bem como sua importância como fármacos ou protótipos e como marcadores químicos de fitoterápicos.

Malaria remains one of the most serious world health problem and the major cause of mortality and morbidity in the endemic regions. Brazil is among the 30 high-burden countries and most of the cases occur in the Legal Amazonian Region. New chemotherapeutical agents are needed for the treatment of malaria. Many plant species are used in traditional medicines of malarious countries and a relatively few number of these have been investigated for evaluation of their antimalarial effect. Still lower is the number of those that have had the active natural compounds isolated and the toxicity determined. This area is, then, of great research interest. discovery project of antimalarial natural products from plants traditionally used to treat malaria must include in vitro and in vivo assays as well as bioguided isolation of active compounds. The final products would be antimalarial chemical entities, potential new drugs or templates for new drugs development, and/or standardized antimalarial extracts which are required for pre-clinical and clinical studies when the aim is the development of effective and safe phythomedicines. This review discusses these two approaches, presents briefly the screening methodologies for evaluation of antimalarial activity and focuses the activity of alkaloids belonging to different structural classes as well as its importance as new antimalarial drugs or leads and chemical markers for phytomedicines.

Wedelia paludosa D.C. (Asteraceae) é uma planta ornamental facilmente encontrada em várias regiões do Brasil, principalmente nos estados de Santa Catarina, São Paulo, Minas Gerais, Bahia e Pernambuco. Objetivando descobrir novas substâncias citotóxicas a partir desta espécie, o extrato hidrometanólico de W. paludosa (HME) e as frações diclorometânica (FD) e aquosa (FA) resultantes de sua partição em CH2Cl2-H2O foram avaliados utilizando-se o bioensaio em Artemia salina. A fração diclorometânica (FD) apresentou a maior atividade citotóxica (CL50 = 140,6 μg/mL), e sua análise por cromatografia líquida de alta eficiência empregando-se fase reversa (FR-CLAE) revelou os ácidos caurenóico (1, 6,22 ± 0,23%) e grandiflorênico (2, 3,22 ± 0,31%) como constituintes majoritários. As amostras HME (CL50 = 980 μg/mL), FD (CLC50 = 140,6 μg/mL), 1 (CL50 = 15,9 μg/mL) e 2 (CL50 = 29,8 μg/mL) foram citotóxicas contra A. salina, enquanto que a fração aquosa (FA, CL50 >> 1000 μg/mL) mostrou-se inativa. Conclui-se que a citotoxidade observada para HME e FD pode ser atribuída à presença dos ácidos caurenóico (1) e grandiflorênico (2) nestes extratos.

Wedelia paludosa D.C. (Asteraceae) is an ornamental species occurring in many regions of Brazil. Aiming to find new cytotoxic compounds, the hydromethanol extract of W. paludosa (HME), as well as the dichloromethane (DF) and water (WF) fractions resulting from its partition, were submitted to the brine shrimp lethality bioassay (BSLB) in order to evaluate their cytotoxicity. Dichloromethane fraction (DF) was shown to be the most cytotoxic fraction (LC50 = 140.6 μg/mL), and its analysis by reversed phase high performance liquid chromatography (RP-HPLC) revealed ent-kaurenoic (1, 6.22 ± 0.23%) and grandiflorenic (2, 3.22 ± 0.31%) acids as important constituents. HME (LC50 = 980 μg/mL), DF (LC50 = 140.6 μg/mL), 1 (LC50 = 15.9 μg/mL) and 2 (LC50 = 29.8 μg/mL) were found to be cytotoxic, while the water fraction (WF, LC50 >> 1000 μg/mL) was inactive. As conclusion, the cytotoxicity observed for HME and DF is mainly due to the presence of 1 and 2 in their constitution.

A reação de biotransformação da digitoxigenina (1) por Cochliobolus lunatus foi investigada. Foram realizados experimentos com duração de 4 dias, que resultaram no isolamento de quatro produtos, cujas estruturas químicas foram elucidadas como sendo 1beta-hidroxidigitoxigenina (2), 7beta-hidroxidigitoxigenina (3), 8beta-hidroxidigitoxigenina (4) e digitoxigenona (5). A obtenção desses produtos nas condições empregadas nunca foi anteriormente descrita. A produção da substância 4 em uma reação de biotransformação também é inédita.

The biotransformation of digitoxigenin (1) by Cochliobolus lunatus was investigated. The biotransformation reaction was carried out in a 4-day process, resulting in the isolation of four products, whose structures were elucidated as 1beta-hydroxydigitoxigenin (2), 7beta-hydroxydigitoxigenin (3), 8beta-hydroxydigitoxigenin (4) and digitoxigenone (5). The production of these derivatives under the employed conditions has never been described so far. This is also the first report on the production of compound 4 by a biotransformation reaction.

Novos derivados oxidados ent-caurânicos e ent-norcaurânicos foram sintetizados a partir do ácido caurenóico. Todos os produtos obtidos foram caracterizados espectroscopicamente.

New oxidized ent-kaurane and ent-norkaurane derivatives were synthezised starting from kaurenoic acid. The spectroscopic characterization of all compounds is reported.

7,2'-Di-hidroxiisoflavona apresentou atividade contra tripomastigotas sanguíneos do Trypanosoma cruzi, agente etiológico da doença de Chagas, o que motivou a síntese de derivados anfifílicos de potencial utilização como quimioprofilático para esterilização de sangue para transfusão. Esta substância foi obtida por desmetilação da 7-hidroxi-2'-metoxiisoflavona, sintetizada via desoxibenzoína, seguindo-se eterificação com epicloridrina e abertura do anel oxirânico com dietilamina para levar à 7-oxipropanolamina, a qual, por tratamento com iodeto de metila, forneceu o sal de amônio correspondente. Nos ensaios in vitro com tripomastigotas sanguíneos do T. cruzi, a 7-hidroxi-2'-metoxiisoflavona foi inativa e a 7-oxipropanolamina foi mais ativa do que a 7,2'-di-hidroxiisoflavona. Já o sal de amônio, não só não eliminou completamente o parasita do sangue como causou lise total dos eritrócitos. Portanto, o sal de amônio não é adequado para o uso como profilático na transmissão do T.cruzi por transfusão sangüínea. A atividade tripanossomicida da 7,2'-di-hidroxiisoflavona e do seu derivado 7-oxipropanolamina estimulam a avaliação in vivo destas substâncias como potenciais quimioterápicos para tratamento da doença de Chagas, sendo necessários alguns gramas destas substâncias que poderão ser obtidos pelos processos simples descritos neste trabalho.

7, 2'-Dihydroxyisoflavone was shown to be active against the bloodstream trypomastigote form of Trypanosoma cruzi, the etiologic agent of Chagas' disease. Amphiphilic derivatives of this isoflavone were synthezised aiming to obtain hydrosoluble compounds of potential use as prophylactic agents to be added to blood for transfusion. This isoflavone was obtained by demethylation of 7-hydroxy-2'-methoxyisoflavone that was synthesized via the intermediate deoxybenzoin. Its reaction with epichlorohydrin, followed by aminolysis with diethylamine, afforded the 7-oxypropanolamine which on treatment with methyl iodide gave the corresponding ammonium salt. The 7-hydroxy-2'-methoxyisoflavone was inactive in the in vitro assays, the 7-oxypropanolamine was more active than 7, 2'-dihydroxyisoflavone while the ammonium salt has not eliminated the parasite from the blood besides causing total lysis of the erythrocytes. The simple synthetic procedures described in the present paper can be used to provide gram quantities of 7, 2'-dihydroxyisoflavone and its 7-oxypropanolamine derivative that should be further investigated in in vivo murine models as potential chemotherapeutic agents for treatment of Chagas' disease.

A biotransformação da digitoxigenina (1) por Fusarium ciliatum foi investigada. O cardenolídeo 1 foi obtido a partir da hidrólise ácida da digitoxina e a reação também forneceu os produtos secundários delta14-15-digitoxigenina (2) e delta8-14-digitoxigenina (3). A reação de biotransformação foi realizada em um período de 5 dias e três produtos foram isolados e identificados a partir de análises espectrométricas: digoxigenina (4), digoxigenona (5) e digitoxigenona (6). A obtenção dos dois últimos cardenolídeos nas condições empregadas é inédita. A investigação da cinética da reação de biotransformação indicou 6 como o primeiro produto a ser formado, seguido dos derivados hidroxilados 4 e 5, sugerindo o envolvimento de enzima distintas na hiroxilação em 12beta e na oxidação em C-3 da digitoxigenina (1). A reação de biotransformação também foi realizada com a digitoxina, mas F. ciliatum se mostrou incapaz de promover sua hidroxilação.

The biotransformation of digitoxigenin (1) by Fusarium ciliatum was investigated. The cardenolide 1 was obtained by the acid hydrolysis of digitoxin and the reaction also afforded two side products, identified as delta14-15-digitoxigenin (2) and delta8-14-digitoxigenin (3) by spectroscopic analysis. The biotransformation reaction was carried out in a 5 days process and three products were isolated and had their structures elucidated as digoxigenin (4), digoxigenone (5) and digitoxigenone (6). The investigation of the biotransformation kinetics disclosed 6 as the first derivative to be formed, followed by the more polar hydroxylated products 4 and 5, suggesting the involvement of different enzymes in 12beta hydroxylation and C-3 oxydation of digitoxigenin (1). The production of 5 and 6 under the employed conditions has never been reported. The biotransformation reaction was also undertaken with digitoxin, but F. ciliatum has been unable to promote its hydroxylation.

O ácido traquilobânico (2) foi incubado com Rhizopus stolonifer, com o objetivo de se sintetizar novos derivados diterpênicos. Após vinte dias, quatro metabólitos foram extraídos, isolados e caracterizados, dos quais dois apresentaram-se hidroxilados nas posições 7beta (3) e 17 (5). Dois derivados rearranjados também foram isolados, os ácidos ent-16beta-hidroxi-caur-11-en-19-óico (4) e 9alfa,16beta-diidroxi-caur-11-en-19-óico (6). O rearranjo do esqueleto traquilobânico levando a derivados do tipo ent-16b-hidroxi-caur-11-eno é condizente com a proposta biogenética que limita a ocorrência deste grupo raro de diterpenos caurânicos somente em plantas contendo representantes com esqueleto traquilobânico. Nenhum relato anterior sobre o isolamento dos diterpenos 5 e 6 foi encontrado na literatura.

A biotransformation experiment of trachyloban-19-oic acid (2) was carried out with Rhizopus stolonifer. After twenty days of reaction, four metabolites were extracted, isolated and characterized: two trachylobane type compounds, the 7beta (3) and the 17 (5) hydroxyl derivatives, and two rearranged ent-kaur-11-en-19-oic acids, the 16beta (4) and the 9alpha,16beta (6) hydroxylated compounds. Products 4 and 5 were isolated as their methyl esters (4a and 5a) after esterification of a mixture containing their corresponding acids. The rearrangement of a trachylobane diterpene leading to ent-16beta-hydroxy-kaur-11-ene derivatives gives support to the biogenetic proposal based on the occurrence of this rare group of kaurenes only in plants containing trachylobane representatives. By the best of our knowledge, this is the first report on the isolation of compounds 5 and 6.