Potent and selective antiplasmodial activity of marine sponges from Bahia state, Brazil.

This study evaluated the in vitro antiplasmodial and cytotoxic effects of 26 extracts from nine marine sponges collected in Salvador, Bahia state, Brazil. All assayed extracts were found to be potently active against Plasmodium falciparum W2 strain, with IC50 values ranging from 0.28 to 22.34 µg mL-1, and weakly cytotoxic against the human cell line WI-26-VA4 with CC50 values > 89 µg mL-1, thus displaying selectivity indices (SI) equal or higher than 17. Interestingly, some SI values exceeded 1,000. The highly potent and selective antiplasmodial activity of the assessed marine sponges is reported for the first time in this study.

Chemical Strategies towards the Synthesis of Betulinic Acid and Its More Potent Antiprotozoal Analogues.

Betulinic acid (BA, 3ß-hydroxy-lup-20(29)-en-28-oic acid) is a pentacyclic triterpene acid present predominantly in Betula ssp. (Betulaceae) and is also widely spread in many species belonging to different plant families. BA presents a wide spectrum of remarkable pharmacological properties, such as cytotoxic, anti-HIV, anti-inflammatory, antidiabetic and antimicrobial activities, including antiprotozoal effects. The present review first describes the sources of BA and discusses the chemical strategies to produce this molecule starting from betulin, its natural precursor. Next, the antiprotozoal properties of BA are briefly discussed and the chemical strategies for the synthesis of analogues displaying antiplasmodial, antileishmanial and antitrypanosomal activities are systematically presented. The antiplasmodial activity described for BA was moderate, nevertheless, some C-3 position acylated analogues showed an improvement of this activity and the hybrid models-with artesunic acid-showed the most interesting properties. Some analogues also presented more intense antileishmanial activities compared with BA, and, in addition to these, heterocycles fused to C-2/C-3 positions and amide derivatives were the most promising analogues. Regarding the antitrypanosomal activity, some interesting antitrypanosomal derivatives were prepared by amide formation at the C-28 carboxylic group of the lupane skeleton. Considering that BA can be produced either by isolation of different plant extracts or by chemical transformation of betulin, easily obtained from Betula ssp., it could be said that BA is a molecule of great interest as a starting material for the synthesis of novel antiprotozoal agents.

Estrogen and Thyroid Hormone Receptor Activation by Medicinal Plants from Bahia, Brazil.

Background: A number of medicinal plants are traditionally used for metabolic disorders in Bahia state, Brazil. The aim of this study was to evaluate the estrogen receptor (ER) and thyroid receptor (TR) activation of crude extracts prepared from 20 plants. Methods: Species were extracted and assayed for receptor activation through both ER and TR gene-reporter assays, using 17ß-estradiol and triiodothyronine (T3), respectively, as the positive controls. Results: Cajanus cajan (Fabaceae), Abarema cochliacarpus (Fabaceae), and Borreria verticillata (Rubiaceae) were able to activate ER as much as the positive control (17ß-estradiol). These three plant species were also assayed for TR activation. At the concentration of 50 µg/mL, C. cajans exerted the highest positive modulation on TR, causing an activation of 59.9%, while B. verticillata and A. cochliacarpus caused 30.8% and 23.3%, respectively. Conclusions: Our results contribute towards the validation of the traditional use of C. cajans, B. verticillata, and A. cochliacarpus in the treatment of metabolic disorders related to ER and TR functions. The gene-reporter assay was proven effective in screening crude plant extracts for ER/TR activation, endorsing this methodology as an important tool for future bioprospection studies focused on identifying novel starting molecules for the development of estrogen and thyroid agonists.

Ferulic Acid and Naturally Occurring Compounds Bearing a Feruloyl Moiety: A Review on Their Structures, Occurrence, and Potential Health Benefits.

The ubiquitous compound 4-hydroxy-3-methoxycinnamic acid, also known as ferulic acid (FA), constitutes a bioactive ingredient of many foods that may offer beneficial effects against disorders related to oxidative stress, including cancer, diabetes, and neurodegenerative diseases. This review discusses the antioxidant properties of FA, establishing relationships to several biological activities already described for this natural product. Next, 387 naturally occurring compounds, all isolated from plants and published between 1990 and 2015, the structures of which bear 1 or more feruloyl moieties, are covered in this review along with their structural formulas, botanical sources, and bioactivities. The compounds' distribution, structural patterns, bioactivities, and perspectives on food research are also succinctly discussed.

Effects of alkaloid extracts of mesquite pod on the products of in vitro rumen fermentation.

The objective of this study was to evaluate the effects of alkaloid extracts of Prosopis juliflora (Sw.) D.C. pods obtained by two extraction methods as compared with sodium monensin on the gas production kinetic, mitigation of methane, and rumen fermentation products using wheat bran or Tifton 85 hay as substrates, by the semi-automatic in vitro gas production technique. A completely randomized design was adopted, and two natural additives were tested made from mesquite pod (alkaloid extract I and alkaloid extract II) at three levels (3.9, 7.9, and 12 µg), sodium monensin 5 µM (positive control), and no inclusion of additives (negative control). The volume of gases produced by the degradation of the fibrous fraction of wheat bran was influenced by the concentration of the extract I added to the medium, and the amounts of 7.9 and 12 µg were equal to monensin at the lowest value. The degradation rate of the fibrous carbohydrates with additive extract I at 12 µg was lower in relation to monensin. When Tifton 85 hay was utilized, alkaloid extract I provided a shorter colonization time as compared with monensin at the added amounts of 7.9 and 12 µg and higher production of gases from the fibrous fraction but without interfering with the total volume of gases produced during 96 h of fermentation of carbohydrates. In the periods of 12 and 24 h of incubation, utilizing alkaloid extract I, the mean values of methane production with wheat bran and Tifton 85 hay were lower than monensin (p < 0.05) when the respective amounts of 7.9 and 12 µg were added. Alkaloid extract I has similar potential to sodium in reducing production of total gases, methane, and the acetate/propionate ratio.

Structure-based drug design studies of the interactions of ent-kaurane diterpenes derived from Wedelia paludosa with the Plasmodium falciparum sarco/endoplasmic reticulum Ca²âº-ATPase PfATP6.

Malaria is responsible for more deaths around the world than any other parasitic disease. Due to the emergence of strains that are resistant to the current chemotherapeutic antimalarial arsenal, the search for new antimalarial drugs remains urgent though hampered by a lack of knowledge regarding the molecular mechanisms of artemisinin resistance. Semisynthetic compounds derived from diterpenes from the medicinal plant Wedelia paludosa were tested in silico against the Plasmodium falciparum Ca2+-ATPase, PfATP6. This protein was constructed by comparative modelling using the three-dimensional structure of a homologous protein, 1IWO, as a scaffold. Compound 21 showed the best docking scores, indicating a better interaction with PfATP6 than that of thapsigargin, the natural inhibitor. Inhibition of PfATP6 by diterpene compounds could promote a change in calcium homeostasis, leading to parasite death. These data suggest PfATP6 as a potential target for the antimalarial ent-kaurane diterpenes.

Structure-based drug design studies of the interactions of ent-kaurane diterpenes derived from Wedelia paludosa with the Plasmodium falciparum sarco/endoplasmic reticulum Ca2+-ATPase PfATP6

Malaria is responsible for more deaths around the world than any other parasitic disease. Due to the emergence of strains that are resistant to the current chemotherapeutic antimalarial arsenal, the search for new antimalarial drugs remains urgent though hampered by a lack of knowledge regarding the molecular mechanisms of artemisinin resistance. Semisynthetic compounds derived from diterpenes from the medicinal plant Wedelia paludosa were tested in silico against the Plasmodium falciparum Ca2+-ATPase, PfATP6. This protein was constructed by comparative modelling using the three-dimensional structure of a homologous protein, 1IWO, as a scaffold. Compound 21 showed the best docking scores, indicating a better interaction with PfATP6 than that of thapsigargin, the natural inhibitor. Inhibition of PfATP6 by diterpene compounds could promote a change in calcium homeostasis, leading to parasite death. These data suggest PfATP6 as a potential target for the antimalarial ent-kaurane diterpenes.

Chemical composition and antinociceptive, anti-inflammatory and antiviral activities of Gallesia gorazema (Phytolaccaceae), a potential candidate for novel anti-herpetic phytomedicines.

ETHNOPHARMACOLOGICAL RELEVANCE: In traditional medicine, teas made from leaves and bark of Gallesia gorazema are used as antispasmodic, anthelmintic, antihemorrhagic and febrifuge agents. Crude leaves of this plant are also employed as a remedy in the treatment of abscesses, orchitis, gonorrhea and for rheumatic pain relief. this study investigates the presumed antinociceptive and anti-inflammatory activities of leaves and roots Gallesia gorazema (Phytolaccaceae) extracts. The most active extract and its isolated compound, a new natural product, are also evaluated against viruses HSV-1 and HSV-2. MATERIALS AND METHODS: In vivo experiments with mice were used to assess the analgesic and anti-inflammatory activities of Gallesia gorazema extracts. Antiviral activity of extracts and the new natural product was investigated by in vitro experiments. RESULTS: Results show that dichloromethanic root (DRE) and ethanolic leaf (ELE) extracts displayed significant antinociceptive and anti-inflammatory activities in in vivo experiments with mice. Both extracts were also assayed against the herpes simplex viruses HSV-1 and HSV-2, but only DRE was highly active, showing a selective antiviral effect against HSV-1. Phytochemical fractionation of DRE led to the isolation of 28-hydroxyoctacosyl ferulate, a novel natural product, which displayed strong antiviral activity against HSV-1 (EC50=21.6 µg/mL) with a selective index above 9, justifying, at least in part, the high selective antiviral activity observed for DRE. CONCLUSION: These results suggest that the plant Gallesia gorazema is a potential candidate for the development of novel anti-herpetic phytomedicines.

Antibacterial activity of the alkaloid-enriched extract from Prosopis juliflora pods and its influence on in vitro ruminal digestion.

The purpose of this study was to assess the in vitro antimicrobial activity of alkaloid-enriched extracts from Prosopis juliflora (Fabaceae) pods in order to evaluate them as feed additives for ruminants. As only the basic chloroformic extract (BCE), whose main constituents were juliprosopine (juliflorine), prosoflorine and juliprosine, showed Gram-positive antibacterial activity against Micrococcus luteus (MIC = 25 µg/mL), Staphylococcus aureus (MIC = 50 µg/mL) and Streptococcus mutans (MIC = 50 µg/mL), its influence on ruminal digestion was evaluated using a semi-automated in vitro gas production technique, with monensin as the positive control. Results showed that BCE has decreased gas production as efficiently as monensin after 36 h of fermentation, revealing its positive influence on gas production during ruminal digestion. Since P. juliflora is a very affordable plant, this study points out this alkaloid enriched extract from the pods of Prosopis juliflora as a potential feed additive to decrease gas production during ruminal digestion.

Synthesis, cytotoxicity and antiplasmodial activity of novel ent-kaurane derivatives.

This paper reports on the syntheses and spectrometric characterisation of eleven novel ent-kaurane diterpenoids, including a complete set of (1)H, (13)C NMR and crystallographic data for two novel ent-kaurane diepoxides. Moreover, the antineoplastic cytotoxicity for kaurenoic acid and the majority of ent-kaurane derivatives were assessed in vitro against a panel of fourteen cancer cell lines, of which allylic alcohols were shown to be the most active compounds. The good in vitro antimalarial activity and the higher selectivity index values observed for some ent-kaurane epoxides against the chloroquine-resistant W2 clone of Plasmodium falciparum indicate that this class of natural products may provide new hits for the development of antimalarial drugs.

iso-Kaurenoic acid from Wedelia paludosa D.C.

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.

iso-Kaurenoic acid from Wedelia paludosa D.C.

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.

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.

Plant-derived antimalarial agents: new leads and efficient phytomedicines. Part II. Non-alkaloidal natural products.

Malaria is still the most destructive and dangerous parasitic infection in many tropical and subtropical countries. The burden of this disease is getting worse, mainly due to the increasing resistance of Plasmodium falciparum against the widely available antimalarial drugs. There is an urgent need for new, more affordable and accessible antimalarial agents possessing original modes of action. Natural products have played a dominant role in the discovery of leads for the development of drugs to treat human diseases, and this fact anticipates that new antimalarial leads may certainly emerge from tropical plant sources. This present review covers most of the recently-published non-alkaloidal natural compounds from plants with antiplasmodial and antimalarial properties, belonging to the classes of terpenes, limonoids, flavonoids, chromones, xanthones, anthraquinones, miscellaneous and related compounds, besides the majority of papers describing antiplasmodial crude extracts published in the last five years not reviewed before. In addition, some perspectives and remarks on the development of new drugs and phytomedicines for malaria are succinctly discussed.

Cytotoxicity of Wedelia paludosa D.C. extracts and constituents / Citotoxidade de extratos e constituintes de Wedelia paludosa D.C

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 percent) and grandiflorenic (2, 3.22 ± 0.31 percent) 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.

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 por cento) e grandiflorênico (2, 3,22 ± 0,31 por cento) 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.

Occurrence, biological activities and synthesis of kaurane diterpenes and their glycosides.

This paper presents a review on kaurane diterpenes and their glycoside derivatives, covering aspects of their occurrence, biological activities and the synthesis of these natural products and their analogues. First, it shows and classifies diterpenes, in accordance with the already established structural criteria in the literature. Then, kaurane diterpenes are presented, focusing on their chemical structures, occurrence in the plant kingdom and their main, recently described, biological activities. Moreover, the most significant works, published between 1964 and November 2006, which describe the total synthesis or structural transformations of some kaurane diterpenes, including either semisynthetic and/or microbiological methodologies, are consisely reviewed. At this point, some general considerations on glycosides are introduced, and kaurane glycosides are presented and discussed on the basis of their toxic importance and occurrence in the plant kingdom, having focused on related aspects of their biological activities and the relationships between these activities and the structural factors of their molecules. Finally, the principal methods of glycosidation by enzymatic and chemical processes are both presented, and a few papers on the synthesis of kaurane glycosides are succinctly discussed.

Synthesis and trypanocidal activity of ent-kaurane glycosides.

Novel ent-kaurane glucosides were synthezised by a Koenigs-Knorr reaction between C17 and C19 alcohols derived from kaurenoic acid and 2,3,4,6-tetra-O-acetyl-glucopyranosyl bromide, followed by the hydrolysis of the acetates. Main products were assayed in vitro and in vivo against blood trypomastigote forms of Trypanosoma cruzi, the aetiological agent of Chagas' disease (American trypanosomiasis). The results allowed to establish structure-activity relationships among these derivatives, as well as pointed out the C19-methylester-C17-O-glucoside as a potential trypanocidal agent, whose trypanocidal profile was shown to be comparable to those of gentian violet and benznidazole.