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In the present study, the hexane extract from branches of Drimys brasiliensis (Winteraceae) displayed potent activity against Schistosoma mansoni parasites (100% mortality of the worms at 200 μg/mL). Bioactivity-guided fractionation afforded, in addition to the previously reported bioactive sesquiterpene 3,6-epidioxy-bisabola-1,10-diene, two chemically related drimane sesquiterpenes-polygodial ( 1 ) and 9-deoxymuzigadial ( 2 ). The anti- S. mansoni effects for compounds 1 and 2 were determined in vitro, with compound 1 demonstrating significant potency (EC 50 value of 10 μM for both male and female worms), while 2 was inactive. Cytotoxicity assays against Vero cells revealed no toxicity for either compound (CC 50 > 200 μM). Additionally, an in silico analysis was conducted using the SwissADME platform for 1 , revealing that this natural sesquiterpene exhibited adherence to several ADME parameters and no PAINS violations. Finally, in vivo studies with S. mansoni -infected mice treated with compound 1 demonstrated a 44.0% reduction in worm burden, accompanied by decreases in egg production of 71.8% in feces and 69.5% in intestines. These findings highlight the potential of polygodial ( 1 ) as a promising prototype for schistosomiasis treatment.

Background: The Parque Estadual do Forno Grande is a fully protected area in the southern Espírito Santo State, Brazil. It belongs to the Atlantic Forest domain, with predominantly dense, ombrophilous, seasonal semi-deciduous forests and herbaceous/shrubby vegetation on rock outcrops. The area is recognised as highly important for conservation, designated as a priority biological area for protecting the Atlantic Forest's biodiversity. Although the importance of Protected Areas in conserving the Atlantic Forest biodiversity is unquestionable, it is crucial to understand the floristic patterns within these regions to develop effective conservation strategies. We utilised national online databases to compile species lists containing relevant information about their biodiversity. The updated list of vascular plants recorded in the Parque Estadual do Forno Grande is available in the "Catálogo de Plantas das Unidades de Conservação do Brasil" and it is presented here with further information on richness, endemism and conservation status., New Information: The Parque Estadual do Forno Grande harbours 958 species of vascular plants, of which 79.2% are angiosperms, 18.4% are ferns and 2.4% are lycophytes. Amongst these species, 44% are endemic to the Atlantic Forest. There are 58 threatened species, of which six are Critically Endangered, 39 are Endangered and 13 are Vulnerable. Amongst the threatened species, 51 are endemic to the Atlantic Forest. The number of records and the species richness in this area are notably high for Atlantic Forest standards. Our findings suggest that floristic inventories of Brazilian Protected Areas are a key contribution to the general perception of how much we still do not know about our flora. It also highlights the necessity of supporting floristic surveys in poorly-known areas, especially those remaining as forest remnants., (Thuane Bochorny, Guilherme M. Antar, Igor H.F. Azevedo, Fernando Bianchi Junior, Tatiana T. Carrijo, Valquiria F. Dutra, André P. Fontana, Claudio N. Fraga, Samuele Gerace, Leandro L. Giacomin, André S.B. Gil, Renato Goldenberg, Diego R. Gonzaga, Gustavo Heiden, Ingrid Koch, Ludovic J.C. Kollmann, Paulo H. Labiak, Duane F. Lima, Gabriel M. Marcusso, Pedro L.R. Moraes, Filipe Torres-Leite, Pedro L. Viana, Rafaela C. Forzza.)

Background: The Atlantic Forest is one of the most diverse and threatened phytogeographical domains in the world. Despite that, it includes regions with poor floristic knowledge, even in protected areas. Although the importance of protected areas in conserving the Atlantic Forest hotspot is undisputed, it is necessary to recognise the floristic richness of these areas to propose effective conservation actions. In this sense, online databases have proved to be a promising tool for compiling species lists with relevant biodiversity information. This study is based on the list of vascular plants of the "Parque Estadual da Pedra Selada", published in the "Catálogo de Plantas das Unidades de Conservação do Brasil". It summarises the species richness, endemism and conservation status of this protected area., New Information: The published list of vascular plants was based on data obtained from herbarium collections available in online databases. A total of 303 species have been recorded for the "Parque Estadual da Pedra Selada," of which 297 are native to Brazil, 78 are endemic to the Brazilian Atlantic Forest, and seven are endemic to the State of Rio de Janeiro. More than 60% of the species are woody, and more than 40% are trees. Eight threatened species (Endangered - EN and Vulnerable - VU), of which five are endemic to the State of Rio de Janeiro, are housed in this protected area. One species was classified as Data Deficient (DD). Our results increase the knowledge of the Atlantic Forest flora in the State of Rio de Janeiro and support effective conservation planning for this protected area., (Isabela Maciel Waga, Andrea Ferreira da Costa, Claudine Massi Mynssen, Eduardo Pinheiro Fernandez, Elsie Franklin Guimarães, Fernanda Saleme, George Azevedo de Queiroz, Guilherme Medeiros Antar, Haroldo Cavalcante de Lima, Hemily Oliveira Marques, Lara Serpa Jaegge Deccache, Leandro Jorge Telles Cardoso, Leandro Lacerda Giacomin, Maria Regina de V. de Vasconcellos Barbosa, Mario Gomes, Marli Pires Morim, Otávio Luis Marques da Silva, Pedro Fiaschi, Pedro Luís Rodrigues de Moraes, Rafaela Campostrini Forzza, Renon Santos Andrade, Thaís Andrade Ferreira Dória, Thiago Serrano de Almeida Penedo, Thuane Bochorny, Marcio Verdi.)

As part of our continuous research for the discovery of bioactive compounds against Trypanosoma cruzi and Leishmania infantum, the alkaloid (6aS)-dicentrine (1) was oxidized to afford (6aS,6S)- (2) and (6aS,6R)- (3) dicentrine-N-oxides. Evaluation of the cytotoxicity against NCTC cells indicated that 2 and 3 are non-toxic (CC 50 >200 μM) whereas 1 demonstrated CC 50 of 52.0 μM. Concerning T. cruzi activity against amastigotes, derivatives 2 and 3 exhibited EC 50 values of 9.9 μM (SI>20.2) and 27.5 μM (SI>7.3), respectively, but 1 is inactive (EC 50 >100 μM). Otherwise, when tested against L. infantum amastigotes, 1 and 3 exhibited EC 50 values of 10.3 μM (SI=5.0) and 12.7 μM (SI>15.7), respectively, being 2 inactive (EC 50 >100 μM). Comparing the effects of positive controls benznidazol (EC 50 =6.5 μM and SI>30.7) and miltefosine (EC 50 =10.2 μM and SI=15.2), it was observed a selective antiparasitic activity to diastereomers 2 and 3 against T. cruzi and L. infantum. Considering stereochemical aspects, it was suggested that the configuration of the new stereocenter formed after oxidation of 1 played an important role in the bioactivity against amastigotes of both tested parasites., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

The hexane extract from twigs of Piper truncatum Vell (Piperaceae) displayed activity against Trypanosoma cruzi and was subjected to chromatographic steps to afford six dibenzylbutyrolactolic lignans, being four knowns: cubebin (1), (-)-9α-O-methylcubebin (2), (+)-9β-O-methylcubebinin (3) and 3,4-dimethoxy-3,4-demethylenedioxycubebin (4) as well as two new, named truncatin A (5) and B (6). Initially, in vitro activity against trypomastigotes was evaluated and compounds 1, 4 and 6 exhibited EC 50 values of 41.6, 21.0 and 39.6 μM, respectively. However, when tested against amastigotes, the relevant clinical form in the chronic phase of Chagas disease, compounds 1-6 displayed activities with EC 50 values ranging from 1.6 to 13.7 μM. In addition, the mammalian cytotoxicity of compounds 1-6 was evaluated against murine fibroblasts (NCTC). Compounds 2, 3 and 4 exhibited reduced toxicity against NCTC cells (CC 50 >200 μM), resulting in SI values of>21.9,>14.5 and>121.9, respectively. Compound 4 showed the highest potency with an SI value twice superior to that determined by the standard drug benznidazole (SI>54.6) against the intracellular amastigotes. These data suggest that lignan 4 can be considered a possible scaffold for designing a new drug candidate for Chagas disease., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

Angiosperms are the cornerstone of most terrestrial ecosystems and human livelihoods 1,2 . A robust understanding of angiosperm evolution is required to explain their rise to ecological dominance. So far, the angiosperm tree of life has been determined primarily by means of analyses of the plastid genome 3,4 . Many studies have drawn on this foundational work, such as classification and first insights into angiosperm diversification since their Mesozoic origins 5-7 . However, the limited and biased sampling of both taxa and genomes undermines confidence in the tree and its implications. Here, we build the tree of life for almost 8,000 (about 60%) angiosperm genera using a standardized set of 353 nuclear genes 8 . This 15-fold increase in genus-level sampling relative to comparable nuclear studies 9 provides a critical test of earlier results and brings notable change to key groups, especially in rosids, while substantiating many previously predicted relationships. Scaling this tree to time using 200 fossils, we discovered that early angiosperm evolution was characterized by high gene tree conflict and explosive diversification, giving rise to more than 80% of extant angiosperm orders. Steady diversification ensued through the remaining Mesozoic Era until rates resurged in the Cenozoic Era, concurrent with decreasing global temperatures and tightly linked with gene tree conflict. Taken together, our extensive sampling combined with advanced phylogenomic methods shows the deep history and full complexity in the evolution of a megadiverse clade., (© 2024. The Author(s).)

In the present work, the hexane extract of aerial parts of Baccharis quitensis Kunth. was subjected to chromatographic fractionation to afford two alkyl phenylpropanoids: n -docosyl ( E)-p -coumarate ( 1 ) and n -tetracosyl (E)-p -coumarate ( 2 ) as well as five diterpenes: ent- kaurenoic acid ( 3 ), grandifloric acid ( 4 ), 15β-senecioyl-oxy- ent -kaur-16-en-19-oic acid ( 5 ), and 15-oxo- ent -kaurenoic acid ( 6 ). Using an ex-vivo assay with macrophages infected with Trypanosoma cruzi , compounds 1 and 2 demonstrated high potency against intracellular amastigotes, with EC 50 values of 7.5 and 6.9 µM, respectively. Compound 6 revealed a moderate potency against T. cruzi , with an EC 50 of 25.6 µM, and compounds 3-5 showed no effectiveness. Additionally, compounds 1-6 compounds presented no toxicity for mammalian cells to the highest tested concentration of 200 µM. Based on potency and the selectivity indexes of 1 , 2 and 6 , these compounds could be future candidates for optimisation studies for the design of prototypes against Chagas disease.

Endemic in 21 countries, Chagas disease, also known as American Trypanosomiasis, is a neglected tropical disease (NTD) caused by the protozoan parasite Trypanosoma cruzi . The available drugs for the treatment of this disease, benznidazole and nifurtimox, are outdated and display severe side effects. Thus, the discovery of new drugs is crucial. Based on our continuous studies aiming towards the discovery of natural products with anti- T. cruzi potential, the MeOH extract from aerial parts of Baccharis sphenophylla Dusén ex. Malme (Asteraceae) displayed activity against this parasite and was subjected to high-performance countercurrent chromatography (HPCCC), to obtain one unreported syn -labdane diterpene - sphenophyllol ( 1 ) - as well as the known compounds gaudichaudol C ( 2 ), ent -kaurenoic acid ( 3 ), hispidulin ( 4 ), eupafolin ( 5 ), and one mixture of di- O -caffeoylquinic acids ( 6 - 8 ). Compounds 1 - 8 were characterized by analysis of nuclear magnetic resonance (NMR) and mass spectrometry (MS) data. When tested against trypomastigote forms, isolated labdane diterpenes 1 and 2 displayed potent activity, with EC 50 values of 20.1 μM and 2.9 μM, respectively. The mixture of chlorogenic acids 6 - 8 , as well as the isolated flavones 4 and 5 , showed significant activity against the clinically relevant amastigotes, with EC 50 values of 24.9, 12.8, and 2.7 μM, respectively. Nonetheless, tested compounds 1 - 8 displayed no cytotoxicity against mammalian cells (CC 50 > 200 μM). These results demonstrate the application of HPCCC as an important tool to isolate bioactive compounds from natural sources, including the antitrypanosomal extract from B. sphenophylla , allowing for the development of novel strategic molecular prototypes against tropical neglected diseases.

Menthinae, one of the five subtribes of Mentheae (Lamiaceae), with ca. 735 species, is represented in Brazil by a wide range of herbs and shrubs. During an investigation of the taxonomic history of the group for the Flora e Funga do Brasil project, several nomenclatural issues with typifications in the group have been identified. This study attempts to resolve them, making suggestions of new types and re-evaluation of synonyms. Thirteen lectotypifications and one neotypification are being proposed, along with the recognition of Thymus selloi Spreng. ex J.A.Schmidt as a nomen nudum . Most of the suggested changes are due to the loss of many of Sellow's types at B during WWII, lack of specific herbaria references and collector numbers in the protologues, or to existence of designated syntypes in the referred collections. Our study is a contribution to the nomenclatural and taxonomic knowledge of Menthinae, providing a stable foundation for future study of its taxonomy, biogeography, and evolution., Competing Interests: Conflicts of interests/Competing interestsAll authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript., (© The New York Botanical Garden 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

This study presents the cytotoxic activity evaluation of the natural diterpenes ent-kaurenoic acid (1) and its 15β-hydroxy (2), 15β-senecioyloxy (3), and 15β-tiglinoyloxy (4) derivatives, isolated from Brazilian native plants, Baccharis retusa and B. lateralis (Asteraceae). Using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) colorimetric assay, it was observed that compound 1 displayed in vitro activity towards the aggressive MDA-MB-231 adenocarcinoma cell line and reduced toxicity against MCF-10A nontumorigenic epithelial cells, indicating expressive selectivity. On the contrary, compounds 2-4 exhibited reduced toxicity and selectivity in both tested cell lines. Based on the chemical structures of compounds 1-4, it is suggested that the presence of additional functional groups at the C-15 position-a hydroxyl group in compound 2 and isomeric isoprene units in compounds 3 and 4-might be responsible for the reduction in the potential/selectivity. In silico studies show, for compounds 1-4, good predictions regarding bioavailability and ADME (absorption, distribution, metabolism, and excretion) properties as well as no alerts for PAINS (pan-assay structures interference). In conclusion, ent-kaurenoic acid (1), a common diterpenoid isolated in high amounts from different plants belonging to the Baccharis genus, has been shown to be a promising cytotoxic agent against an aggressive adenocarcinoma cell line (MDA-MB-23) and, if well exploited, could be used as a scaffold in the development of molecular prototypes for the treatment of breast cancer., (© 2022 Deutsche Pharmazeutische Gesellschaft.)

Background: The Atlantic Forest is one of the most threatened biomes in the world. Despite that, this biome still includes many areas that are poorly known floristically, including several protected areas, such as the "Floresta Nacional do Rio Preto" ("Flona do Rio Preto"), located in the Brazilian State of Espírito Santo. This study used a published vascular plant species list for this protected area from the "Catálogo de Plantas das Unidades de Conservação do Brasil" as the basis to synthesise the species richness, endemism, conservation and new species occurrences found in the "Flona do Rio Preto"., New Information: The published list of vascular plants was based on field expeditions conducted between 2018 and 2020 and data obtained from herbarium collections available in online databases. Overall, 722 species were documented for the "Flona do Rio Preto", 711 of which are native to Brazil and 349 are endemic to the Atlantic Forest. In addition, 60 species are geographically disjunct between the Atlantic and the Amazon Forests. Most of the documented species are woody and more than 50% of these are trees. Twenty-three species are threatened (CR, EN and VU), while five are Data Deficient (DD). Thirty-two species are new records for the State of Espírito Santo. Our results expand the knowledge of the flora of the Atlantic Forest and provide support for the development of new conservation policies for this protected area., (Anderson Alves-Araújo, Marina M Moreira, Tatiana T Carrijo, Lúcia G Lohmann, Adriana Q Lobão, Alana F Scheidegger, Aline D Firmino, Aline Vieira de Melo Silva, Álvaro Nepomuceno, Amélia C Tuler, André MA Amorim, André LC Moreira, Braz AP Cosenza, Brenno G Sossai, Christian Silva, Claudia R Lopes, Daniele Monteiro, Dayvid R Couto, Duane F Lima, Eduardo C Dalcin, Eliana Ramos, Elton J Lírio, Fatima Salimena, Felipe Alves de Oliveira, Fernanda RM Fraga, Filipe Torres-Leite, Guilherme M Antar, Gustavo H Shimizu, Haroldo C Lima, Herison Medeiros, Jaquelini Luber, Jheniffer A Christ, João Lanna, João Paulo F Zorzanelli, Joelcio Freitas, José FB Pastore, José IM Melo, Juliana Paula-Souza, Juliana RPM Oliveira, Leandro C Pederneiras, Leandro Freitas, Leandro L Giacomin, Leonardo D Meireles, Luis AE Silva, Luiz JS Pinto, Luiz Menini Neto, Marcelo Trovó, Mário L Garbin, Marli P Morim, Michel Ribeiro, Nelson TL Pena, Paulo H Labiak, Pedro H Cardoso, Pedro L Viana, Pedro LR Moraes, Quélita S Moraes, Raquel F Zorzanelli, Renara N Amaral, Renata C Asprino, Renato Goldenberg, Ricardo Magnago, Ricardo S Couto, Sandrine C Dutra, Saúl E Hoyos-Gómez, Tamara AF Vieira, Thiago B Flores, Valquíria F Dutra, Víctor S Miranda, Vitor C Manhães, Rafaela C Forzza.)

Background: In the present work the bioactivity-guided fractionation of n-hexane extract from aerial parts of Baccharis sphenophylla (Asteraceae) against trypomastigote forms of Trypanosoma cruzi was performed., Purpose: To evaluate the antitrypanosomal potential of diterpenes ent‑kaurenoic (1), grandifloric (2). and 15β-tiglinoyloxy‑ent-kaurenoic (3) acids, isolated from n-hexane extract from aerial parts of B. sphenophylla, and elucidate their mechanism of action against T. cruzi. METHODS/STUDY DESIGN: n-Hexane and MeOH extracts from aerial parts of B. sphenophylla were prepared and caused, respectively, 100% and 50% of death of trypomastigote forms of T. cruzi. Based on these results, the n-hexane extract was subjected to bioactivity-guided fractionation procedures to afford three related ent‑kaurane diterpenoids (1-3). Based on spectrofluorometric assays and flow cytometry analysis, the mechanism of action of compounds 1 and 3 was investigated., Results: Compounds 1 and 3, isolated from n-hexane extract from aerial parts of B. sphenophylla, showed potent activity against parasites with EC 50 values of 10.6 μM (SI > 18.8) and 2.4 μM (SI = 34.8), respectively. On the other hand, compound 2 was inactive against trypomastigotes. In mechanism of action studies using the fluorescent probe SYTOX Green, the plasma membrane permeability was unaltered after treatment with compounds 1 and 3, but compound 1 induced a depolarization of the plasma membrane electric potential (ΔΨp). No substantial alterations were observed in the mitochondria after treatment with compound 3, but a transient hyperpolarization of the mitochondrial membrane potential (ΔΨm) by compound 1. Despite the increased ATP levels induced by compounds 1 and 3, no alterations of ROS and Ca 2+ levels were registered. However, both compounds promoted a time-dependent alkalinization of the acidocalcisomes, probably contributing to an osmotic imbalance of the cell. In silico physicochemical studies of compounds 1-3 suggested that lipophilicity and molecular complexity may play an important role in the antitrypanosomal activity. Moreover, no pan-assay interference compounds (PAINS) alerts were detected for compounds 1-3., Conclusion: Obtained data indicated that the isolated ent‑kaurane diterpenes from n-hexane extract from aerial parts of B. sphenophylla, especially compound 3, could be considered interesting prototypes for further modifications aiming the discovery of new hits against T. cruzi., (Copyright © 2021 Elsevier GmbH. All rights reserved.)

The hexane extract from aerial parts Baccharis sphenophylla Dusén ex Malme (Asteraceae) displayed activity against amastigote forms of Trypanossoma cruzi and was subjected to chromatographic steps to afford one unreported - 7α-hydroxy-ent-abieta-8(14),13(15)-dien-16,12β-olide (1) and three known diterpenes - ent-kaur-16-en-19-oic acid, (2), grandifloric acid (3), and 15β-tiglinoyloxy-ent-kaur-16-en-19-oic acid (4), two sesquiterpenes - spathulenol (5) and oplopanone (6) - as well as hexacosyl p-coumarate (7). Isolated compounds were characterized by NMR and ESI-HR-MS spectra and were evaluated in vitro for activity against amastigote forms of the parasite T. cruzi - the relevant clinical form in the chronic phase of Chagas disease. In addition, the activity of compounds 1-7 against NCTC cells was evaluated. Compounds 1 and 7 showed effectiveness with EC 50 values of 21.3 and 16.9 μM, respectively. Both compounds also exhibited reduced toxicity against NCTC cells (CC 50 >200 μM) with SI values higher than 9.4 and 11.9. Obtained results suggest that the new ent-abietane diterpene 1 and alkyl coumarate 7 could be used as prototypes for the development of novel and selective semisynthetic derivatives against intracellular forms of T. cruzi., (© 2021 Wiley-VHCA AG, Zurich, Switzerland.)

The search for the pharmacophore of a bioactive compound, crucial for drug discovery studies, involves the adequate arrangement of different atoms in the molecule. As part of a continuous work aiming discovery of new drug candidates against the protozoan parasite Trypanosoma cruzi, the hexane extract of Hydrocotyle bonariensis was subjected to a bioactivity-guided fractionation to afford two chemically related dibenzylbutyrolactone lignans - hinokinin (1) and hibalactone (2). Compounds 1 and 2 showed activity against trypomastigote with EC 50 values of 17.0 and 69.4 μM, respectively. Compound 1 was also active against the clinically relevant form of the parasite, amastigotes, displaying an EC 50 value of 34.4 μM. The structure-activity relationship (SAR) indicated that the absence of the double bond at C-7 is a crucial feature for the increment of the antiparasitic activity. The lethal action of the most potent compound 1 was investigated in the trypomastigotes. The fluorescent-based assay with SYTOX Green demonstrated a significant alteration of the plasma membrane permeability of the parasite. Additionally, compound 1 demonstrated no significant hemolytic activity in mice erythrocytes at 200 μM. To search the pharmacophore, three different simplified compounds - 3,4-methylenedioxydihydrocinnamic acid (3), 3,4-methylenedioxydihydrocinnamic alcohol (4) and 3,4-methylenedioxycinnamic acid (5) - were prepared and tested against T. cruzi. These derivatives displayed EC 50 values of 37.2 (3), 25.8 (4) and 73.5 (5) μM against trypomastigotes, and 41.3 (3) and 48.2 (4) μM against amastigotes, whereas compound 5 was inactive. Except for compound 2, which resulted in a CC 50 value of 114.5 μM, all compounds showed no mammalian cytotoxicity at 200 μM. An in silico ADMET study was performed and predicted values demonstrated an acceptable drug-likeness profile for compounds 1-5. Despite the minor reduction in the potency, the simplified derivatives retained the antitrypanosomal activity against the intracellular amastigotes, even with 95 % reduction of their molecular weight. Additionally, in silico studies suggested them as more soluble compounds, making these simplified structures promising scaffolds for optimization studies in Chagas disease., (© 2021 Wiley-VHCA AG, Zurich, Switzerland.)

Phenylphenalenones, metabolites found in Schiekia timida (Haemodoraceae), are a class of specialized metabolites with many biological activities, being phytoalexins in banana plants. In the constant search to solve the problem of glyphosate and to avoid resistance to commercial herbicides, this work aimed to investigate the phytotoxic effect of the methanolic extract of S. timida seeds. The chemical composition of the seed extract was directly investigated by NMR and UPLC-QToF MS and the pre- and post-emergence phytotoxic effect on a eudicotyledonous model ( Lactuca sativa ) and a monocotyledonous model ( Allium cepa ) was evaluated through germination and seedling growth tests. Three concentrations of the extract (0.25, 0.50, and 1.00 mg/mL) were prepared, and four replicates for each of them were analyzed. Three major phenylphenalenones were identified by NMR spectroscopy: 4-hydroxy-anigorufone, methoxyanigorufone, and anigorufone, two of those reported for the first time in S. timida . The presence of seven other phenylphenalenones was suggested by the LC-MS analyses. The phenylphenalenone mixture did not affect the germination rate, but impaired radicle and hypocotyl growth on both models. The effect in the monocotyledonous model was statistically similar to glyphosate in the lowest concentration (0.25 mg/mL). Therefore, although more research on this topic is required to probe this first report, this investigation suggests for the first time that phenylphenalenone compounds may be post-emergence herbicides.

Twigs of Nectandra barbellata were extracted using a solution of the ionic liquid 1-butyl-3-methylimidazolium bromide (BMImBr) in H 2 O, assisted by microwave (MAE). After successive chromatographic steps, one sesquiterpene, costic acid, and three new related lactones, (R)- 3(7)- Z -3-hexadec-21-enylidene-5-(hydroxymethyl)tetrahydrofuran-2-one ( 1 ), (R)- 3(7)- Z -3-hexadecylidene-5-(hydroxymethyl)tetrahydrofuran-2-one ( 2 ), and (R)- 3(7)- Z -3-docosylidene-5-(hydroxymethyl)tetrahydrofuran-2-one ( 3 ), were isolated. After structural elucidation using IR, UV, HRESIMS, NMR, ECD, and VCD, compounds 1-3 were tested against trypomastigote forms of Trypanosoma cruzi . The mechanism of action of bioactive isolated compounds was studied using different fluorescent-based approaches to investigate alterations of the plasma membrane, permeability/electric potential (ΔΨ p ), reactive oxygen species levels, mitochondria (electric membrane potential, ΔΨ m /ATP levels), Ca 2+ levels, and pH of the acidocalcisomes. In addition, in silico studies predicted no resemblance to pan assay interference compounds (PAINS).

One new aporphine, dicentrine-β-N-oxide (1), together with five related known alkaloids dehydrodicentrine (2), predicentrine (3), N-methyllaurotetanine (4), cassythicine (5), and dicentrine (6) were isolated from the leaves of Ocotea puberula (Lauraceae). Antiprotozoal activity of the isolated compounds was evaluated in vitro against trypomastigote forms of Trypanosoma cruzi. Among the tested compounds, alkaloid 1 exhibited higher potential with EC 50 value of 18.2 μM and reduced toxicity against NCTC cells (CC 50 >200 μM - SI>11.0), similar to positive control benznidazole (EC 50 of 17.7 μM and SI=10.7). Considering the promising results of dicentrine-β-N-oxide (1) against trypomastigotes, the mechanism of parasite death caused by this alkaloid was investigated. As observed, this compound reached the plasma membrane electric potential directly after 2 h of incubation and triggered mitochondrial depolarization, which probably leads to trypomastigote death. Therefore, dicentrine-β-N-oxide (1), reported for the first time in this work, can contribute to future works for the development of new trypanocidal agents., (© 2021 Wiley-VHCA AG, Zurich, Switzerland.)

Background: Brazilian protected areas are essential for plant conservation in the Atlantic Forest domain, one of the 36 global biodiversity hotspots. A major challenge for improving conservation actions is to know the plant richness, protected by these areas. Online databases offer an accessible way to build plant species lists and to provide relevant information about biodiversity. A list of land plants of "Parque Nacional do Caparaó" (PNC) was previously built using online databases and published on the website "Catálogo de Plantas das Unidades de Conservação do Brasil." Here, we provide and discuss additional information about plant species richness, endemism and conservation in the PNC that could not be included in the List. We documented 1,791 species of land plants as occurring in PNC, of which 63 are cited as threatened (CR, EN or VU) by the Brazilian National Red List, seven as data deficient (DD) and five as priorities for conservation. Fifity-one species were possible new ocurrences for ES and MG states., New Information: "Parque Nacional do Caparaó" houses 8% of the land plant species endemic to the Brazilian Atlantic Forest, including 6% of its angiosperms, 31% of its lycophytes and ferns and 14% of its avascular plants. Twelve percent of the threatened species listed for the State of Espírito Santo and 7% listed for the State of Minas Gerais are also protected by PNC. Surprisingly, 79% of the collections analysed here were carried out in Minas Gerais, which represents just 21% of the total extension of the Park. The compiled data uncover a huge botanical collection gap in this federally-protected area., (Marina M Moreira, Tatiana T Carrijo, Anderson G Alves-Araújo, Alessandro Rapini, Alexandre Salino, Aline D Firmino, Aline P Chagas, Ana F A Versiane, André M A Amorim, Andrews V S da Silva, Amélia C Tuler, Ariane L Peixoto, Bethina S Soares, Braz A P Cosenza, Camila N Delgado, Claudia R Lopes, Christian Silva, Daniel E F Barbosa, Daniele Monteiro, Danilo Marques, Dayvid R Couto, Diego R Gonzaga, Eduardo Dalcin, Elton John de Lirio, Fabrício S Meyer, Fátima R G Salimena, Felipe A. Oliveira, Filipe S Souza, Fernando B Matos, Gabriel Depiantti, Guilherme M Antar, Gustavo Heiden, Henrique M Dias, Hian C F Sousa, Isabel T F V Lopes, Isis M Rollim, Jaquelini Luber, Jefferson Prado, Jimi N Nakajima, João Lanna, João Paulo F Zorzanelli, Joelcio Freitas, José F A Baumgratz, Jovani B S Pereira, Juliana R P M Oliveira, Kelly Antunes, Lana S Sylvestre, Leandro C Pederneiras, Leandro Freitas, Leandro L Giacomin, Leonardo D Meireles, Leonardo N Silva, Luciana C Pereira, Luís Alexandre E Silva, Luiz Menini Neto, Marcelo Monge, Marcelo L O Trovó, Marcelo Reginato, Marcos E G Sobral, Mario Gomes, Mário L Garbin, Marli P Morim, Nayara D Soares, Paulo H E Labiak, Pedro L Viana, Pedro H Cardoso, Pedro L R Moraes, Pedro B Schwartsburd, Quélita S Moraes, Raquel F Zorzanelli, Renara Nichio-Amaral, Renato Goldenberg, Samyra G Furtado, Thamara Feletti, Valquíria F Dutra, Vinícius R Bueno, Vinícius A O Dittrich, Rafaela C Forzza.)

Praziquantel is the only available drug to treat schistosomiasis, and therefore, urgent studies must be performed to identify new anthelmintic agents. This study reports the anthelmintic evaluation of two related ent -kaurane diterpenes isolated from aerial parts of Baccharis lateralis (Asteraceae), ent -kaur-16-en-19-oic acid ( 1 ) and 15β-senecioyl-oxy- ent -kaur-16-en-19-oic acid ( 2 ) against Schistosoma mansoni in vitro and in a murine model of schistosomiasis. Both compounds exhibited in vitro activity with lethal concentration 50% (LC 50 ) values of 26.1 μM ( 1 ) and 11.6 μM ( 2 ) as well as reduced toxicity against human cell lines, revealing a good selectivity profile, mainly with compound 2 (selectivity index > 10). Compound 2 also decreased egg production and caused morphological alterations in the parasite reproductive system. In mice infected with S. mansoni , oral treatment with compound 2 at 400 mg/kg, the standard dose used in this model of schistosomiasis, caused a significant reduction in a total worm burden of 61.9% ( P < 0.01). S. mansoni egg production, a key mechanism for both transmission and pathogenesis, was also markedly reduced. In addition, compound 2 achieved a significant reduction in hepatosplenomegaly. Therefore, the diterpene 15β-senecioyl-oxy- ent -kaur-16-en-19-oic acid ( 2 ) has an acceptable cytotoxicity profile and is orally active in a murine schistosomiasis model.

In the present work, the oxoaporphine alkaloid dicentrinone was isolated, for the first time, from leaves of Ocotea puberula (Lauraceae). This alkaloid exhibited antiparasitic activity against trypomastigote forms of Trypanosoma cruzi (IC 50 of 16.4 ± 1.7 μM), similar to the positive control benznidazole (IC 50 of 18.7 ± 4.1 μM), reduced mammalian cytotoxicity (CC 50  > 200 μM), and a selectivity index (SI) higher than 12. These results were correlated with the effects observed using cellular membrane models, represented by 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE), in Langmuir monolayers. Dicentrinone was incorporated in the films, submitted to lateral compression, and characterized by tensiometry. As observed in compression-decompression and time-stability curves, dicentrinone expanded the lipid monolayers, decreased the compressional modulus of the film, and reduced the stability of the monolayer. Brewster Angle Microscopy and interfacial Infrared Spectroscopy showed that dicentrinone causes the monolayers to be segregated in phases, and to increase the number of gauche/trans conformers ratio for the lipid acyl methylene groups, indicating configurational disorder. As a result, dicentrinone caused a disturbance in the cell membrane models, altering the physicochemical properties of the lipid surface such as thermodynamic, rheological, morphological, and structural aspects. These results can be useful to understand the interactions between dicentrinone and lipid biological surfaces at the molecular level., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Schistosomiasis is one of the most important parasitic infections in terms of its negative effects on public health and economics. Since praziquantel is currently the only drug available to treat schistosomiasis, there is an urgent need to identify new anthelmintic agents. Piplartine, also known as piperlongumine, is a biologically active alkaloid/amide from peppers that can be detected in high amounts in the roots of Piper tuberculatum. Previously, it has been shown to have in vitro schistosomicidal effects. However, its anthelmintic activity in an animal host has not been reported. In the present work, in vivo antischistosomal properties of isolated piplartine were evaluated in a mouse model of schistosomiasis infected with either adult (patent infection) or juvenile (pre-patent infection) stages of Schistosoma mansoni. A single dose of piplartine (100, 200 or 400 mg/kg) or daily doses for five consecutive days (100 mg/kg/day) administered orally to mice infected with schistosomes resulted in a reduction in worm burden and egg production. Treatment with the highest piplartine dose (400 mg/kg) caused a significant reduction in a total worm burden of 60.4% (P < 0.001) in mice harbouring adult parasites. S. mansoni egg production, a process responsible for pathology in schistosomiasis, was also significantly inhibited by piplartine. Studies using scanning electron microscopy revealed substantial tegumental alterations in parasites recovered from mice. Since piplartine has well-characterized mechanisms of toxicity, is easily available, and is cost-effective, our results indicate that this bioactive molecule derived from medicinal plants could be a potential lead compound for novel antischistosomal agents., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

As part of our continuous studies on prospecting metabolites from Brazilian plant species with pharmacologic activity against Trypanosoma cruzi, the n-hexane extract from twigs of Nectandra barbellata (Lauraceae) was subjected to a bioactivity-guided fractionation to afford the sesquiterpene costic acid. As results, costic acid induced a trypanocidal effect with IC 50 of 37.8 and 7.9 μM to trypomastigotes and intracellular amastigotes, respectively. When tested in L929 cells, no cytotoxicity was detected in the highest tested concentration (CC 50  > 200 μM), resulting in SI values >5 and >25 to trypomastigotes and amastigotes, respectively. Based on these promising results against T. cruzi, a mechanistic study of the parasite death was investigated. The flow cytometry analysis of costic acid-treated parasites showed depolarization of the plasma membrane electric potential. Spectrofluorimetrical analysis and transmission electron microscopy showed no evidence of plasma membrane permeability alteration of trypomastigotes, but strong ultrastructural damage, evidenced by large vacuoles. Although Ca 2+ and reactive oxygen species (ROS) levels were unaltered after short time incubation with costic acid, it rapidly affected the mitochondria, leading to a depolarized potential of the membrane, reducing the ATP levels. In silico studies of costic acid showed good predictions for drug-likeness, with adherence to Lipinskís rules of five (RO5), good ADMET properties and no alerts for Pan-Assay Interference Compounds (PAINS). Therefore, costic acid demonstrated promising activity against T. cruzi parasites, with high selectivity to intracellular amastigotes. Considering the lethal action of costic acid in affecting a vital and unique organelle as the mitochondria, it could be considered a new hit compound for future drug design studies for Chagas disease., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: From a previous screening of Brazilian biodiversity for antitrypanosomal activity, the n-hexane extract from twigs of Nectandra oppositifolia (Lauraceae) demonstrated in vitro activity against Trypanosoma cruzi., Purpose: To perform the isolation and chemical characterization of bioactive compounds from n-hexane extract from twigs of N. oppositifolia and evaluate their therapeutical potential as well as to elucidate their mechanism of action against T. cruzi., Methods/study Design: Bioactivity-guided fractionation of the n-hexane extract from twigs of N. oppositifolia afforded three related butenolides: isolinderanolide D (1), isolinderanolide E (2) and secosubamolide A (3). These compounds were evaluated in vitro against T. cruzi (trypomastigote and amastigote forms) and against NCTC (L929) cells for mammalian cytotoxicity. Additionally, phenotypic analyzes of compounds-treated parasites were performed: alterations in the plasma membrane permeability, plasma membrane electric potential (ΔΨ p ), mitochondrial membrane potential (ΔΨ m ) and induction of ROS., Results: Compounds 1-3 were effective against T. cruzi, with IC 50 values of 12.9, 29.9 and 12.5 µM for trypomastigotes and 25.3, 10.1 and 12.3 µM for intracellular amastigotes. Furthermore, it was observed alteration in the mitochondrial membrane potential (ΔΨ m ) of parasites treated with butenolides 1-3. These compounds caused no alteration to the parasite plasma membrane, and the deregulation of the mitochondria might be an early event to cell death. In addition, in silico studies showed that all butenolides were predicted to be non-mutagenic, non-carcinogenic, non hERG blockers, with acceptable human intestinal absorption, low inhibitory promiscuity with the main five CYP isoforms, and with high metabolic stability. Otherwise, tested butenolides showed unfavorable blood-brain barrier penetration (BBB+)., Conclusion: Our results demonstrated the anti-T. cruzi effects of compounds 1-3 isolated from N. oppositifolia and indicated that the lethal effect of these compounds in trypomastigotes of T. cruzi could be associated to the alteration in the mitochondrial membrane potential (ΔΨ m )., (Copyright © 2018 Elsevier GmbH. All rights reserved.)

Baccharis retusa, a medicinal Brazilian plant from Asteraceae, has been used in Brazilian folk medicine to treatment of several illnesses, including parasitic diseases. Bioactivity-guided fractionation of the n-hexane extract from the aerial parts of B. retusa resulted in the isolation and characterization of three active related diterpenes: ent-15β-senecioyl-oxy-kaur-16-en-19-oic acid (1), ent-kaur-16-en-19-oic (2) and ent-16-oxo-17-nor-kauran-19-oic (3) acids. The structures of isolated compounds were defined by spectroscopic analysis, including NMR and HRESIMS. Antitrypanosomal activity of 1-3 was performed against cell-derived trypomastigotes using the colorimetric resazurin assay. The obtained results demonstrated that isolated compounds displayed a reduced toxicity against NCTC cells and were effective against the trypomastigote forms of T. cruzi with IC 50 values of 3.8μM (1), 75.3μM (2) and 44.2μM (3). Additionally, compound 3 displayed activity against amastigote forms of T. cruzi with IC 50 of 83.2μM. Compound 1 displayed the highest selectivity index (SI) when considered the trypomastigote forms, and its effect in the plasma membrane of parasite was evaluated using the fluorescent probe SYTOX Green. A considerable permeabilization (57%) in the membrane of the parasite was observed when compared to the untreated trypomastigotes. These data demonstrate, for the first time, the antitrypanosomal activity and mechanism of action of 1 and related compounds 2 and 3, obtained from aerial parts of B. retusa., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Guarea macrophylla is a Brazilian plant species that has been used in folk medicine to treat a range of diseases. Our ongoing work focuses on the discovery of new bioactive natural products derived from Brazilian flora. The current study describes the identification of cytotoxic compounds from the EtOH extract of leaves from G. macrophylla using bioactivity-guided fractionation. This approach resulted in the isolation and characterization of four compounds: cycloart-23 E -ene-3 β ,25-diol ( 1 ), (23 S *,24 S *)-dihydroxycicloart-25-en-3-one ( 2 ), isopimara-7,15-diene-2 α ,3 β -diol ( 3 ), and isopimara-7,15-dien-3 β -ol ( 4 ), in which 2 and 3 are identified as new derivatives. In vitro assays were conducted to evaluate the cytotoxic activity of compounds 1 - 4 against a panel of cancer cell lines and to determine the possible mechanism(s) related to the activity of the compounds on B16F10Nex2 cells. The most active compound 1 induced cytotoxic effects on tumor cells, with IC 50 values of 18.3, 52.1, and 58.9 µM against HL-60, HeLa, and B16F10-Nex2 tumor cells, respectively. Furthermore, it was observed in melanoma cells that compound 1 induced several specific apoptotic hallmarks, such as morphological changes in the cell shape structure, nuclear DNA condensation, specific chromatin fragmentation, and disruption in the mitochondrial membrane potential, which are related to the intrinsic apoptotic pathway., Competing Interests: Conflict of Interest: The authors declare no conflict of interest., (Georg Thieme Verlag KG Stuttgart · New York.)