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Dimeric flavonoids, also called biflavonoids, are bioactive compounds that exhibit various activities described in the literature, including antibacterial, antifungal, antiviral, anti-inflammatory, analgesic, antioxidant, vasorelaxant, and anticancer properties. This work focuses on the anticancer action of naturally occurring dimeric flavonoids against prostate and breast cancer, as well as on the mechanisms of action involved in their activity and presents the most current information on this subject in the literature. In the present review, we summarize the latest findings on the antiproliferative activity of 33 dimeric flavonoid-based compounds selected from recently published studies. The tests conducted were in silico and in vitro and demonstrated the cytotoxic activity potential of biflavonoids against prostate and breast tumor cells. Biflavonoids were capable of interfering with the migration and replication of cancer cells and their mechanism of action is related to cell death pathways, especially apoptosis, necrosis, and ferroptosis. These compounds decreased mitochondrial membrane potential and significantly increased intracellular levels of reactive oxygen species (ROS). Additionally, they significantly upregulated the expression of p21, Bax, and cleaved caspase-3, while downregulating Bcl-2 and caspase-3 levels, indicating their cell death mechanism of action is through the Bcl-2/Bax/cleaved caspase-3 pathway and cell cycle arrest. The biflavonoids here related have shown promising anticancer activity and are considered potential drug candidates for prostate and breast cancer treatment.

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The SARS-CoV-2 mutation and the limitation of the approved drug against COVID-19 are still a challenge in many country healthcare systems and need to be affronted despite the set of vaccines to prevent this viral infection. To contribute to the identification of new antiviral agents, the present study focused on natural products from an edible fruit with potential inhibitory effects against the SARS-CoV-2 main protease (Mpro). First, LC-ESIMS analysis of Platonia insignis fruits was performed and showed the presence of biflavonoids and benzophenones in the seed and pulp, respectively. Then, maceration and chromatographic purification led to the identification of two triglycerides (1 and 2) alongside chamaejasmine (3) and volkensiflavone (4) from the seed and isogarcinol (5) and cycloxanthochymol (6), from the pulp. Compounds 1-6 after evaluating their inhibitory against Mpro, displayed from no to significant activity. Compound 5 was the most potent with an IC50 value of 0.72 µM and was more active than the positive control, Ebselen (IC50 of 3.4 µM). It displayed weak and no cytotoxicity against THP-1 (CC50 of 116.2 µM) and Vero cell lines, respectively. Other active compounds showed no cytotoxicity against THP-1. and Vero cell lines. Molecular docking studies revealed interactions in the catalytic pocket between compound 5 and amino acid residues that composed the catalytic dyads (His 41 and Cyst 145).

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Pancreatic cancer is an aggressive disease with a high death rate and is difficult to treat. This disease, in the most cases, is asymptomatic until it progresses to an advanced stage. Therefore, the search for bioactive molecules is urgent to combat pancreatic cancer. Then, this work analyzed the interaction potential of agathisflavone and amentoflavone molecules against the HIF1 target using the ADMET, molecular docking, and molecular dynamics simulations. More recent drug-likeness filters that combine physicochemical and physiological parameters have shown that high polar surface area (TPSA > 75 Å2) drives biflavonoids out of the toxic drug space of Pfizer dataset. Regarding the pharmacokinetic descriptors, it was possible to notice that Amentoflavone showed a better order of passive cell permeability (Papp = 8 × 10-6 cm/s) and better metabolic stability, biotransformed by aromatic hydroxylation reactions by the CYP3A4 isoenzyme on the human liver, that favor its hepatic clearance. The molecular docking and molecular dynamics simulations indicated the high interaction potential and stability between the ligands analyzed (highlighted the amentoflavone molecule), respectively. The MM/GBSA calculations showed that the amentoflavone ligand registered the highest ΔG binding value of -32.6957 kcal/mol with the HIF1 target. Then, this molecule may be used as a potential inhibitor of pancreatic cancer. In this perspective, the present work represents an initial step in the virtual bioprospecting a pharmacological tool for treating of pancreatic cancer.Communicated by Ramaswamy H. Sarma.

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This paper describes the evaluation of the antimicrobial and hemolytic activity of the hexane, dichloromethane, ethyl acetate and methanol extracts from seeds and epicarps of Garcinia madruno; as well garcinol, morelloflavone and volkensiflavone isolated from the same species. In the preliminary test of bacterial susceptibility, hexane extracts from seeds and epicarps and the three compounds tested only displayed inhibitory growth effect against Gram-positive bacteria. The minimum inhibitory concentrations of extract and compounds ranging from 86.6 to 1253.4 µg/mL. The hemolytic activity was assessed; however, except for the methanol extract from seeds, none of the samples studied induced hemolysis. Thus, our results suggest that extracts and compounds from G. madruno have the potential to be used in the control of pathologies associated to Gram-positive bacteria. This is the first report of the antimicrobial and hemolytic activity of extracts of different polarity obtained from seeds and epicarps of this edible species.

El presente artículo describe la evaluación de la actividad antimicrobiana y hemolítica de los extractos de hexano, diclorometano, acetato de etilo y metanol, obtenidos de la semilla y el epicarpio de Garcinia madruno; así como de garcinol, morelloflavona y volkensiflavona; aislados de la misma especie. En el ensayo de susceptibilidad bacteriana, tanto el extracto de hexano obtenido a partir de la semilla y el epicarpio, y los tres compuestos aislados, únicamente mostraron actividad inhibitoria del crecimiento contra bacterias Gram-positivas. La concentración mínima inhibitoria presentó valores entre 86.6 y 1253.4 µg/mL. También se estableció la actividad hemolítica; sin embargo, con excepción del extracto metanólico obtenido a partir de las semillas, ninguna de las muestras evaluadas indujo hemólisis. Por lo tanto, los resultados sugieren que los extractos y compuestos de G. madruno tienen el potencial de ser usados en el control de bacterias Gram-positivas asociadas a diversas patologías. Este es el primer reporte de actividad antimicrobiana y hemolítica de extractos de diferente polaridad obtenidos de las semillas y epicarpios de esta especie comestible.

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ETHNOPHARMACOLOGICAL RELEVANCE: The tribe Symphonieae (Clusiaceae) encompasses 48 species accommodated in seven genera (Lorostemon, Montrouziera, Moronobea, Pentadesma, Platonia, Symphonia and Thysanostemon). Parts of these plants, mainly the exudates and the seeds oil are useful for different purposes, especially for treating dermatological conditions. In addition to the role in the folk medicine, some species are of great economic and cultural importance for native people from different continents. AIM OF THE REVIEW: The goal of this review is to critically summarize the current knowledge on systematics, ethnobotanical, chemical and pharmacological aspects of species from the tribe Symphonieae, as well as to provide support for future taxonomic and phylogenetic studies on the Clusiaceae family. MATERIALS AND METHODS: The available information was gathered from many different databases (Web of Science, ScienceDirect, Scopus, Pubmed, ChemSpider, SciFinder, ACS Publications, Wiley Online Library, Useful Tropical Plants Database, Google Scholar). Additional data from books, theses and dissertations were also included in this review. RESULTS: Chemical studies of Symphonieae have demonstrated that the genera are a source of benzophenones, xanthones and biflavonoids. Components as sesquiterpenoids, triterpenoids, flavonoids, free fatty acids, among others, have also been reported. Extracts and compounds isolated from a variety of species have been exhibiting antimicrobial, cytotoxic and antiprotozoal activities, corroborating part of their medicinal uses. In addition, certain species produce edible fruits and a kind of "butter" with economic importance. All species produce exudate, which often has great relevance in the daily lives of local people. CONCLUSION: Several species of Symphonieae have potential therapeutic applications and some of them have been investigated to scientifically validate their popular uses. In addition, a number of species have proved to be a rich source of promising pharmacologically active compounds. Finally, the value of fruits, exudate and butter, for instance, should serve as a stimulus for the sustainable development of products that aim to take advantage of these natural resources.

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RESUMEN Varios virus con genoma de ARN en fases iniciales de la infección realizan la translocación de proteínas al interior del núcleo de la célula hospedera mediante la vía de las importinas α1. Este transporte es fundamental para el éxito de la replicación viral y se ha convertido en un blanco para la búsqueda y desarrollo de nuevos antivirales. El objetivo de este estudio fue determinar y caracterizar interacciones entre la Agatisflavona, Amentoflavona, Punicalina con el sitio mayor de unión de las Importinas α1 humanas mediante el análisis in silico del acoplamiento molecular y simulaciones de dinámica molecular. Las pruebas de acoplamiento molecular se realizaron entre estos fitoconstituyentes y la estructura de la importina α1 humana. Las afinidades de interacción fueron detectadas con la Agatisflavona, Amentoflavona y Punicalina (ΔG b = -8,8, -9,1 y -8,8 kcal.mol-1 respectivamente), con afinidades de interacción específicamente a los dominios ARM2-ARM5 (sitio mayor de unión) de las importinas α1. Las simulaciones de dinámica molecular revelaron interacciones significativamente favorables (P<0,001) con los ligandos Agatisflavona y Amentoflavona (ΔG b = -18,60±0,35 y -22,55±2,41 kcal.mol-1) mientras que la Punicalina registró mayores valores de energía de interacción (ΔG b = -5,33±1,72 kcal.mol-1). Los hallazgos obtenidos en este estudio computacional sugieren que las moléculas Agatisflavona y Amentoflavona presentan interacciones favorables con el sitio mayor de unión de las Importinas α1, en comparación a lo registrado con la Punicalina, sin embargo, se recomienda realizar ensayos in vitro a modo de confirmar estas observaciones.

ABSTRACT Several RNA-viruses during early stages of infection perform the translocation of proteins into the nucleus of host cell by the importin α1 pathway. This transport is essential for viral replication success and has become a target to search and development new antivirals. The objective of this study was to determine and characterize interactions between Agathisflavone, Amentoflavone and Punicalin with the major binding site of human importins α1 by in silico analysis of molecular docking and molecular dynamics simulations. Molecular docking tests were performed between these phytoconstituents and the structure of human importin α1. Interaction's affinity was detected with the Agathisflavone, Amentoflavone and Punicalin (ΔG b = -8.8, -9.1 and -8.8 kcal.mol-1 respectively), with binding affinity to ARM 2-ARM 5 domains (major binding site) of importins α1. Molecular dynamics simulations revealed significantly favorable interactions (P<0.001) with the ligands Agatisflavone and Amentoflavone (ΔG b = -18.60 ± 0.35 and -22.55 ± 2.41 kcal.mol-1) meanwhile Punicalin showed higher values of interaction free energy (ΔG b = -5.33 ± 1.72 kcal.mol-1). The findings obtained suggest that Agathisflavone and Amentoflavone could favorably interact to the major binding site of Importins α1 compared to that registered with Punicalin, however, it is recommended to perform in vitro assays to confirm these observations.

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Brazilian traditional medicine has explored the antiviral properties of many plant extracts, including those from the Brazilian pepper tree, Schinus terebinthifolius. In the present study, we investigated the chemical composition and anti-mayaro virus (MAYV) activity of S. terebinthifolius fruit. Extensive virucidal activity (more than 95%) was detected for the ethyl acetate extract and the isolated biflavonoids. From the ethyl acetate extract of Schinus terebinthifolius fruits, two bioflavonoids were isolated ((2S, 2″S)-2,3,2″,3″-tetrahydroamentoflavone and agathisflavone), which showed strong virucidal activity against Mayaro virus. Furthermore, several other compounds like terpenes and phenolics were identified by hyphenated techniques (GC-MS, LC-MS and HPLC-UV), as well as by mass spectrometry. Immunofluorescence assay confirmed antiviral activity and transmission electron microscopy revealed damage in viral particles treated with biflavonoids. The data suggest the direct action of the extract and the biflavonoids on the virus particles. The biflavonoids tetrahydroamentoflavone and agathisflavone had strong virucidal activity and reduced MAYV infection. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13337-021-00698-z.

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BACKGROUND: The arthropod-borne Mayaro virus (MAYV) causes "Mayaro fever," a disease of medical significance, primarily affecting individuals in permanent contact with forested areas in tropical South America. Recently, MAYV has attracted attention due to its likely urbanization. There are currently no licensed drugs against most mosquito-transmitted viruses. Punica granatum (pomegranate) fruits cultivated in Brazil have been subjected to phytochemical investigation for the identification and isolation of antiviral compounds. In the present study, we explored the antiviral activity of pomegranate extracts in Vero cells infected with Mayaro virus. METHODS: The ethanol extract and punicalagin of pomegranate were extracted solely from the shell and purified by chromatographic fractionation, and were chemically identified using spectroscopic techniques. The cytotoxicity of the purified compounds was measured by the dye uptake assay, while their antiviral activity was evaluated by a virus yield inhibition assay. RESULTS: Pomegranate ethanol extract (CC50 = 588.9, IC50 = 12.3) and a fraction containing punicalagin as major compound (CC50 = 441.5, IC50 = 28.2) were shown to have antiviral activity (SI 49 and 16, respectively) against Mayaro virus, an alphavirus. Immunofluorescence analysis showed the virucidal effect of pomegranate extract, and transmission electron microscopy (TEM) revealed damage in viral particles treated with this extract. CONCLUSIONS: The P. granatum extract is a promising source of antiviral compounds against the alphavirus MAYV and represents an excellent candidate for future studies with other enveloped RNA viruses.

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Flavonoids, synthesized by plants across all families and therefore found in a huge variety, possess a diverse range of pharmacological properties. Direct antibacterial and synergistic activities as well as the inhibition of several bacterial virulence factors are known. Besides the mode of action, it is important to understand the structure-activity relationship to identify key structural characteristics. This study aimed to identify biflavonoids with antibacterial activity from Schinus terebinthifolius Raddi fruits. The purified biflavonoids were characterized in terms of their antibacterial effects. We found that the activity of biflavonoids, including agathisflavone (AGF), amentoflavone (AMF), and tetrahydroamentoflavone (THAF), was dependent on their chemical configuration and degree of oxidation, with THAF showing the highest activity on planktonic cells. Additionally, biofilm formation and composition were strongly influenced by THAF. Even slight differences in the chemical structure have fundamental effects on the activity of isolated biflavonoids. This suggests a specific binding of these substances in bacteria and thus enables detailed investigations of the mode of action in the future.

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The objectives of this work were to determine the phenolic profile of Schinus terebinthifolius and Schinus molle fruits and to develop a reliable method for the differentiation of these two similar spices both known as pink pepper. Anthocyanins, biflavonoids and gallotannins, some of which are reported for the first time in these species, were identified by UHPLC-UV/vis-MS/MS. Consideration of the relative and absolute amounts of phenolics as well as indicator compounds from 18 samples revealed that the relative amounts of anthocyanins and biflavonoids are the most trustworthy parameters. Principal component analysis and cluster analysis (CA) allowed a grouping of the samples according to their species, showing that the anthocyanins are most important for the identification of species. As a result, authentication of the two Schinus species can be accomplished by UHPLC analysis of the relative amounts of anthocyanins combined with CA.

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