Natural and Semi synthetic Antimalarial Compounds: Emphasis on the Terpene Class.

Malaria is one of the most important tropical diseases since more than 40% of the world population is at risk. This disease is endemic to more than 100 nations and remains one of the main leading causes of death in children less than five years of age worldwide. Natural product-derived compounds have played a major role in drug discovery, often as prototypes to obtain more active semi synthetic derivatives. Antimalarial pharmacotherapy is a significant example of plant-derived medicines, such as quinine and artemisinin. This review highlights studies on terpenes and their semi synthetic derivatives from natural sources with antimalarial activity reported in the literature during eleven years (2002-2013). A total of 114 compounds are found among terpenes and their semi synthetic derivatives. Cytotoxicity of the compounds is also found in this review. Furthermore, the physicochemical properties of the terpenes addressed are discussed based on seven well established descriptors, which provide a useful source for the elaboration of a terpene library of antimalarial compounds.

Antimicrobial activity of fermented Theobroma cacao pod husk extract.

Theobroma cacao L. contains more than 500 different chemical compounds some of which have been traditionally used for their antioxidant, anti-carcinogenic, immunomodulatory, vasodilatory, analgesic, and antimicrobial activities. Spontaneous aerobic fermentation of cacao husks yields a crude husk extract (CHE) with antimicrobial activity. CHE was fractioned by solvent partition with polar solvent extraction or by silica gel chromatography and a total of 12 sub-fractions were analyzed for chemical composition and bioactivity. CHE was effective against the yeast Saccharomyces cerevisiae and the basidiomycete Moniliophthora perniciosa. Antibacterial activity was determined using 6 strains: Staphylococcus aureus, Staphylococcus epidermidis, and Bacillus subtilis (Gram-positive) and Pseudomonas aeruginosa, Klebsiella pneumoniae, and Salmonella choleraesuis (Gram-negative). At doses up to 10 mg/mL, CHE was not effective against the Gram-positive bacteria tested but against medically important P. aeruginosa and S. choleraesuis with a minimum inhibitory concentration (MIC) of 5.0 mg/mL. Sub-fractions varied widely in activity and strongest antibacterial activity was seen with CHE8 against S. choleraesuis (MIC of 1.0 mg/mL) and CHE9 against S. epidermidis (MIC of 2.5 mg/mL). All bioactive CHE fractions contained phenols, steroids, or terpenes, but no saponins. Fraction CHE9 contained flavonoids, phenolics, steroids, and terpenes, amino acids, and alkaloids, while CHE12 had the same compounds but lacked flavonoids.

Micellar aggregates of saponins from Chenopodium quinoa: characterization by dynamic light scattering and transmission electron microscopy.

Entire seeds of Chenopodium quinoa Willd are a rich protein source and are also well-known for their high saponin content. Due to their amphiphily quinoa saponins are able to form intricate micellar aggregates in aqueous media. In this paper we study the aggregates formed by self-association of these compounds from two quinoa saponin fractions (FQ70 and FQ90) as well as several distinctive nanostructures obtained after their complexation with different ratios of cholesterol (CHOL) and phosphatidylcholine (PC). The FQ70 and FQ90 fractions were obtained by reversed-phase preparative chromatography. The structural features of their resulting aggregates were determined by Dynamic Light Scattering (DLS) and Transmission Electron Microscopy (TEM). Novel nanosized spherical vesicles formed by self-association with mean diameter about 100-200 nm were observed in FQ70 aqueous solutions whereas worm-like micelles an approximate width of 20 nm were detected in FQ90 aqueous solutions. Under experimental conditions similar to those reported for the preparation of Quillaja saponaria ISCOM matrices, tubular and ring-like micelles arose from FQ70:CHOL:PC and FQ90:CHOL:PC formulations, respectively. However, under these conditions no cage-like ISCOM matrices were observed. The saponin composition of FQ70 and FQ90 seems to determine the nanosized structures viewed by TEM. Phytolaccagenic acid, predominant in FQ70 and FQ90 fractions, is accountable for the formation of the nanosized vesicles and tubular structures observed by TEM in the aqueous solutions of both samples. Conversely, ring-like micelles observed in FQ90:CHOL:PC complexes can be attributed to the presence of less polar saponins present in FQ90, in particular those derived from oleanolic acid.

Quillaja brasiliensis saponins are less toxic than Quil A and have similar properties when used as an adjuvant for a viral antigen preparation.

In this study, a preparation of saponins (QB-90U) extracted from leaves of Quillaja brasiliensis collected in Uruguay was evaluated as a vaccine adjuvant by comparison with alum and the well known saponin-based adjuvant, Quil A. The haemolytic activity and cellular toxicity of the saponin preparations were also evaluated. QB-90U was only slightly haemolytic and showed a low cytotoxicity when compared to Quil A. The adjuvant properties of QB-90U were assayed by sub-cutaneous immunization of mice with a preparation of inactivated bovine herpesvirus 5 (BoHV-5) either with no adjuvant or adjuvanted with QB-90U, Quil A or alum. Serum levels of anti-BoHV-5 IgG, IgG1, IgG2a, IgG2b and also IgG3 were significantly increased by QB-90U and were of the same order as those elicited by Quil A. Furthermore, high titres of neutralizing antibodies were found to be present in the serum of immunized animals from both groups. The cellular response induced by QB-90U did also reproduce the one elicited by Quil A. In fact, a robust DTH response was observed in mice immunized with both saponin preparations; as well as increased splenocytes levels of Th1-type cytokines, namely IFN-γ and IL-2. Taken together, the above results confirm and extend our previous observation regarding the similarity of the responses elicited by Quil A and the saponin preparation from Q. brasiliensis (Fleck et al., 2006) and indicate that QB-90U is worth of further studies as a safe and potent vaccine adjuvant.

Immunoadjuvant and anti-inflammatory plant saponins: characteristics and biotechnological approaches towards sustainable production.

Saponins can be classified as triterpenoid (C30) or steroidal (C27), based on their carbon nucleus (aglycone). Sugar residues are linked to the aglycone, conferring an amphiphilic nature on these molecules, which is relevant for their biological activities. Saponins include a large variety of molecules that find several applications in pharmacology. Saponins have been shown to display immunoadjuvant, anti-inflammatory, antiplatelet, hypocholesterolemic, antitumoral, anti-HIV, antibacterial, insecticide, fungicide and anti-leishmanial activities. Anti-inflammatory medicines are increasingly demanded to treat various forms of arthritis in aging and obese populations and to help reduce the doses and duration of conventional corticotherapy with less side effects and without immunosuppression. The vaccine market for both human and veterinary uses is close to US$ 15 billion, progressively inflated by the recurrent threat of global pandemics.This paper provides an overview of recent advances (main focus on the last five years) on plant saponins that show anti-inflammatory and/or immunoadjuvant activities: source plants, isolation procedures, mechanism of action and biotechnological approaches towards sustainable production of bioactive saponins. Special attention is given to ginseng and Quillaja saponins. Strategies based on plant cultivation, cell and tissue culture, elicitation, and metabolic engineering for improved production of saponins are described. Future directions for research in the field and strategies to overcome bottlenecks are also discussed.

Alum-type adjuvant effect of non-haemolytic saponins purified from Ilex and Passiflora spp.

Five saponins purified from the leaves of three Ilex species (saponins 1 and 2 from I. dumosa; saponin 3 from I. argentina; saponin 4 from I. paraguariensis) and from Passiflora alata (saponin 5) were evaluated for their in vitro haemolytic activity and in vivo immunostimulatory ability in a mouse model using tetanus toxoid (TT) as a model antigen. The assayed saponins showed very weak or no haemolytic activity over the tested concentration range. Mice were immunized twice with TT formulated with pure saponins 1-5, or with a mixture of saponins from Quillaja saponaria, aluminum hydroxide gel or saline, which were used as controls. The elicited humoral response was evaluated by means of the time course of specific serum antibody levels up to day 131 post-priming (total IgG and isotypes); the cellular response was tested through a delayed-type hypersensitivity (DTH) assay. The assayed saponins, in particular saponins 3 and 5, showed an adjuvant effect similar to that of alum for all tested parameters. The immunostimulating potential of these compounds deserves further investigation, especially taking into account that some Ilex spp. and Passiflora alata are native crops of widespread use and economical importance in Latin America.

Identification and stability of a new bichalcone in Achyrocline satureioides spray dried powder.

A new chemical structure, the 4,2',4",2'''-tetrahydroxy-6',6'''-dimethoxy-4'-O-4'''- bichalcone, named achyrobichalcone was isolated and identified from an Achyrocline satureioides spray-dried powder (SDP80). The thermal and photo stability of this new compound as well as that of the main polyphenols present in the spray dried powder, quercetin, luteolin, 3-O-metylquercetin and the corresponding kinetics of degradation are reported. In the long-term testing (30 +/- 2 degrees C/75 +/- 5% RH, 12 months), the total polyphenols contained in SDP80 demonstrated to be stable, remaining higher than 90% after a 12 month exposure. The photo stability testing revealed that all polyphenols were stable for 48 h when SDP80 was conditioned in amber or transparent flasks and exposed to UV-C radiation (light express LE UV, 254 nm, 30W). In contrast, when unprotected, the polyphenols demonstrated to be sensitive to both, thermal stress testing (80 +/- 2 degrees C), for 14 days and to UV-C radiation. Luteolin showed to be the most stable against UVC light and 3-O-methylquercetin against temperature. The achyrobichalcone demonstrated to be the more unstable against both, temperature and light. The kinetics of polyphenol thermal degradation (80 +/- 2 degrees C, 49 days) and photodegradation (UV-C radiation, 96 h) followed, 2nd and 1st order reaction, respectively.

Passiflora alata and Passiflora edulis spray-dried aqueous extracts inhibit inflammation in mouse model of pleurisy.

The aqueous leaves extracts of Passiflora alata (100-300 mg/kg, i.p.) and Passiflora edulis (100-1000 mg/kg, i.p.) possess a significant antiinflammatory activity on carrageenan-induced pleurisy in mice. Treatment with the extracts inhibited leukocyte migration and reduced the formation of exudate. Moreover, a significant inhibition of myeloperoxidase and adenosine-deaminase activities was observed at the doses tested (100 or 250 mg/kg, i.p.). At the same doses, a significant decrease of serum C-reactive protein was observed.

Phenotypic plasticity in Passiflora suberosa L.(Passifloraceae): induction and reversion of two morphs by variation in light intensity.

Leaf morphology may vary considerably even within a branch of Passiflora suberosa plants. Leaves are of a typical green type in shaded areas, but in open fields turn into violet, and apparently have greater thickness and trichome density. The proximate causes and the adaptive meaning, if any, for the existence of the violet morph are still unknown. By cultivating P. suberosa clones under two light regimes (total and partial exposure to sunlight), we consecutively induced (first year) and then reversed (second year) the appearance of the violet morph. We evaluated the corresponding changes in morpho-anatomic and chemical leaf characteristics. Plants that were grown under partial sunlight had a greater size and did not alter their green color, but those grown under total sunlight changed into violet, were smaller in size and their leaves were tougher, thicker, and had a greater number of trichomes. The violet morph had increased anthocyanins and phenolic derivatives. It also showed cellular hypertrophy, a greater number of cell layers in the mesophyll, and a lignified pericycle. Since these morphs are interchangeable by changing light conditions, we inferred that they are not determined by genotypic diversity, but are mainly a result of a physiological response to light stress, and thus part of P. suberosa phenotypic plasticity.

Phenotypic plasticity in Passiflora suberosa L.(Passifloraceae): induction and reversion of two morphs by variation in light intensity / Plasticidade fenotípica em Passiflora suberosa L. (Passifloraceae): indução e reversão de duas formas pela variação na intensidade luminosa

Leaf morphology may vary considerably even within a branch of Passiflora suberosa plants. Leaves are of a typical green type in shaded areas, but in open fields turn into violet, and apparently have greater thickness and trichome density. The proximate causes and the adaptive meaning, if any, for the existence of the violet morph are still unknown. By cultivating P. suberosa clones under two light regimes (total and partial exposure to sunlight), we consecutively induced (first year) and then reversed (second year) the appearance of the violet morph. We evaluated the corresponding changes in morpho-anatomic and chemical leaf characteristics. Plants that were grown under partial sunlight had a greater size and did not alter their green color, but those grown under total sunlight changed into violet, were smaller in size and their leaves were tougher, thicker, and had a greater number of trichomes. The violet morph had increased anthocyanins and phenolic derivatives. It also showed cellular hypertrophy, a greater number of cell layers in the mesophyll, and a lignified pericycle. Since these morphs are interchangeable by changing light conditions, we inferred that they are not determined by genotypic diversity, but are mainly a result of a physiological response to light stress, and thus part of P. suberosa phenotypic plasticity.

A morfologia das folhas de Passiflora suberosa pode variar consideravelmente mesmo dentro dos ramos de um dado espécime. P. suberosa ocorre tipicamente em áreas sombreadas e as folhas são verdes. Porém, em áreas abertas, onde há maior incidência de luz solar, as folhas são de coloração roxa, aparentemente mais duras e com grande densidade de tricomas. As possíveis causas e o significado adaptativo da manifestação destas características ainda são desconhecidas. Com base no cultivo de clones de P. suberosa sob dois regimes de luz solar (incidência total e parcial), nós consecutivamente induzimos (primeiro ano) e então revertemos (segundo ano) o aparecimento da forma roxa. As mudanças nas características morfológicas e químicas das formas verde e roxa foram avaliadas. As plantas que foram cultivadas sob incidência parcial de luz solar apresentaram maior tamanho dos ramos e não alteraram a cor verde das folhas. As plantas que foram cultivadas sob incidência total dos raios solares apresentaram coloração roxa, maior dureza, espessura e pilosidade. A forma roxa apresentou alto teor de antocianinas e derivados fenólicos. As plantas exibiram hipertrofia celular, maior número de camadas celulares no mesofilo e lignificação do periciclo. Considerando que as formas são intercambiáveis perante a mudança na intensidade luminosa, nós inferimos que elas não resultam da diversidade genotípica, mas sim de uma resposta fisiológica ao estresse luminoso e, dessa forma, parte da plasticidade fenotípica de P. suberosa.

Constituents from leaves of Quillaja brasiliensis.

A new abietane diterpene, the 19-O-beta-D-glucopyranoside of 16-hydroxylambertic acid was isolated from the leaves of Quillaja brasiliensis together with a known prosapogenin (3-O-beta-D-glucuronopyranosyl-quillaic acid), quercetin, and rutin. The new compound was identified by chemical and spectroscopic methods.

Triterpenes and saponins from Ilex psammophila.

Two new saponins were isolated from the leaves of Ilex psammophila. Their structure was established by chemical and spectroscopic methods as 28-O-beta-D-glucopyranosylester of 20(S)-ilexgenin A ([structure: see text]) and 28-O-beta-D-glucopyranosylester of 20(S)-3beta,19alpha,24-trihydroxyurs-12-ene-23, 28-dioic acid ([structure: see text]).

Gênero Pfaffia: aspectos químicos, farmacológicos e implicações para o seu emprego terapêutico / Pfaffia: available chemical and pharmacological data and their implications for its therapeutical use

Os relatos encontrados na literatura científica sobre a composição química e atividades farmacológicas do gênero Pfaffia spp. são apresentados. Os estudos sobre esse gênero são ainda bastante escassos, sendo assim, o uso racional de espécies de Pfaffia, com finalidade terapêutica ainda depende de conhecimento aprofundado de suas propriedades farmacológicas e do desenvolvimento de tecnologias de produção e controle de qualidade.

This review summarizes available chemical and pharmacological data about Pfaffia genre. Scientific studies about these species are still lacking, and their therapeutical rational use depends on the availability of more informations about their pharmacological properties and the development of production and control quality technologies.

Comparative pharmacological study of hydroethanol extracts of Passiflora alata and Passiflora edulis leaves.

Several species of the genus Passiflora, known in Brazil as "maracujá", have widespread use in folk medicine as sedatives and tranquillizers. The anxiolytic activity of hydroethanol extracts of P. alata and P. edulis leaves was evaluated using the elevated plus-maze test. The extracts presented anxiolytic activity in dosages around 50, 100 and 150 mg/kg.

Tilirosídeo em Croton gnaphalii BAlLL

O gênero Croton possui seiscentas espécies e é originário de regiões tropicais. Croton gnaphelil é conhecida no sul do Brasil como infalivina, sendo utilizada popularmente nos distúrbios hepáticos. A substância majoritária presente nas partes aéreas desta planta foi isolada e identificada através de métodos espectroscópicos, sendo identificada como um glicosídeo acilado, o canferol‑3‑O‑(6"‑O‑p‑cumaroil)‑β‑D‑glicopyranose, também chamado de tilirosídeo.

Croton genus comprises six hundred species being native in tropical forests. Croton gnaphalliis popularly known as "infalivina" in South of Brazil and it is traditionally used for hepatic disorders. The major compound from aerial parts of this plant was isolated and its structure elucidated through spectroscopic analysis. It was identified as an acylglycoside, kaempferol‑3‑O‑(6"‑O‑p‑coumaroyl)‑ β ‑D‑glucopyranoside, known as tiliroside.

Triterpenoid glycosides and a triterpene from Ilex brevicuspis.

Two saponins and a sapogenin were isolated from the leaves of Ilex brevicuspis. Their structures were established by means of spectroscopic methods as brevicuspisaponin 1 (3-O-alpha-L-arabinopyranosyl-20(S)-19 alpha,24-dihydroxyursolic acid), brevicuspisaponin 2 (3-O-alpha-L-arabinopyranosyl-20(S)-19 alpha,23,24-trihydroxyursolic acid) and 23-methylester of 20(S)-3 beta,19 alpha,24-trihydroxyurs-12-en-23,28-dioic acid.

Matesaponin 5, a highly polar saponin from Ilex paraguariensis.

The structure of matesaponin 5, a novel saponin isolated from the leaves of the Ilex paraguariensis, was established as ursolic acid-3-0-{beta-D-glucopyranosyl-(1->3)-[alpha-L-rhamnopyranosyl-(1->2)]-alpha-L- arabino pyranosyl}-(28->1)-beta-D-glucopyranosyl-(1->4)-beta-D-glucopyranosyl-(1 ->6)-beta-D-glucopyranosyl] ester.

Triterpenoid saponins from Ilex paraguariensis.

The leaves of Ilex paraguariensis have yielded three new saponins named matesaponins 2, 3, and 4 [1-3], which have been characterized by chemical and nmr methods as ursolic acid 3-O-[beta-D-glucopyranosyl-(1-->3)-[alpha-L-rhamnopyranosyl- (1-->2)]]-alpha-L-arabinopyranosyl]-(28-->1)-beta-D-glucopyranosyl ester, ursolic acid 3-O-[beta-D-glucopyranosyl-(1-->3)-alpha-L-arabinopyranosyl]-(28-- >1)- [beta-D-glucopyranosyl-(1-->6)-beta-D-glucopyranosyl]ester, and ursolic acid 3-O-[beta-D-glucopyranosyl-(1-->3)-[alpha-L- rhamnopyranosyl-(1-->2)]]-alpha-L-arabinopyranosyl]-(28-->1)-[beta -D- glucopyranosyl-(1-->6)-beta-D-glucopyranosyl]ester, respectively.