Antifungal and phytotoxic activity of benzoic acid derivatives from inflorescences of Piper cumanense.

The Piperaceae family is recognized for its diverse biological properties such as antifungal, antibacterial, cytotoxic and insecticidal activities. Phytochemical investigation of inflorescences from P. cumanense led to the isolation and identification of a new 4-chromanone called oxocumanensic acid, along with five known benzoic acid derivatives. The antifungal activity was evaluated against six phytopathogenic fungi by a mycelium growth inhibition test. All compounds were active against the phytopathogenic fungi, showing a greater activity against fungi of Fusarium genus. Finally, phytotoxicity was evaluated in the extract and its chemical constituents, finding that the natural substances are less toxic than the positive control.

Isoquinoline alkaloids from the roots of Zanthoxylum rigidum as multi-target inhibitors of cholinesterase, monoamine oxidase A and Aß1-42 aggregation.

Multifactorial neurodegenerative disorders such as Alzheimer's disease (AD) are considered a growing public health problem due the rising incidence and low effectiveness of current treatments [6]. Since pharmacotherapy based on a single target has been insufficient for drug development in complex diseases, the emerging multi-target approach is a promising strategy for the search of new anti-AD drug candidates. Herein described natural isoquinoline alkaloids were investigated for multi-target activity on key mechanisms associated with the AD's pathogenesis, i.e. cholinergic depletion, beta amyloid (Aß) aggregation and oxidative stress. Alkaloid isolation from root extract of Zanthoxylum rigidum was carried out using multi-step chromatography and TLC-bioautography against acetylcholinesterase (AChE) giving eight purified isoquinoline alkaloids. Isolated compounds were tested for inhibitory activity against cholinesterase (AChE and BChE), monoamine oxidase (MAO-A and B) and Aß aggregation. Our study revealed two benzophenanthridine alkaloids, nitidine (5) and avicine (7), as the most potent multi-target candidates. Both showed dual cholinesterase inhibition, being more active against AChE over BChE, with IC50 values in sub-micromolar range in AChE. Kinetic analysis with cholinesterase showed, that both compounds are reversible-mixed inhibitors, where avicine (7) presented highest potency with Ki values of 0.063 µM (EeAChE), 0.511 µM (HrAChE) and 0.123 µM (EqBChE). In addition, these alkaloids presented moderate Aß1-42 anti-aggregation activity and MAO-A inhibition with IC50 values between 0.5 and 2 µM. Our findings suggest that avicine (7) is a promising natural compound and multifunctional candidate representing a suitable starting point for the development of new therapeutic agents for Alzheimer's disease.

Metabolomic profiling of Zanthoxylum species: Identification of anti-cholinesterase alkaloids candidates.

The isolation of bioactive compounds from natural sources is a key step in drug discovery and development, however, this procedure is usually expensive and difficult due to the complexity and the limited amounts of the metabolites in the extracts. Thus, rational or targeting isolations are becoming more popular to reduce the bottlenecks in bioactive natural products research. In this study, we used a LC-MS-based metabolomic approach and biochemometric statistical tools (PCA and OPLS-DA) to identify potential anti-cholinesterase alkaloids predictors in Zanthoxylum genus (Rutaceae). For this purpose, 41 alkaloid extracts from nine Colombian Zanthoxylum species were screened by UHPLC-UV-HRMS and inhibitory activity against Acetylcholinesterase (AChE) and Butyrylcholinesterase (BChE). Based on the screening results, a multivariate statistical analysis (MVA) and selection of anti-cholinesterase candidates were performed using the S-plot from the OPLS-DA model. The supervised analysis (OPLS-DA) paring the anti-cholinesterase screening and LC-HRMS data showed at least 11 ChE inhibition markers which could have contributed in the differentiation of active and inactive extracts. The predictors were tentatively identified by comparing chromatographic retention times (Rt) and accurate mass and MS2 fragmentation patterns. In general, the inhibition markers correspond to four types of isoquinoline alkaloids: tetrahydroprotoberberines, protoberberines, dihydrobenzophenanthridines and benzophenanthridines. The most active extracts from Z. schreberi and Z. monophylum showed the highest presence of berberine and chelerythrine, previously reported as cholinesterase inhibitors. Thus, to validate the results of the OPLS-DA model, three alkaloids from the bark of Z. schreberi (identified as berberine, chelerythrine and columbamine) were bio-directed isolated, and all of them showed strong inhibition against both enzymes. These findings support our statistical models and contribute to the rational search of anticholinesterase alkaloids. Therefore, LC-MS-based metabolomic approach combined with chemometric statistical analysis are shown as useful tools for the isolation of targeted bioactive natural products, contributing to improve the research and development stages of lead compounds.

XIAP as a Target of New Small Organic Natural Molecules Inducing Human Cancer Cell Death.

X-linked inhibitor of apoptosis protein (XIAP) is an emerging crucial therapeutic target in cancer. We report on the discovery and characterisation of small organic molecules from Piper genus plants exhibiting XIAP antagonism, namely erioquinol, a quinol substituted in the 4-position with an alkenyl group and the alkenylphenols eriopodols A-C. Another isolated compound was originally identified as gibbilimbol B. Erioquinol was the most potent inhibitor of human cancer cell viability when compared with gibbilimbol B and eriopodol A was listed as intermediate. Gibbilimbol B and eriopodol A induced apoptosis through mitochondrial permeabilisation and caspase activation while erioquinol acted on cell fate via caspase-independent/non-apoptotic mechanisms, likely involving mitochondrial dysfunctions and aberrant generation of reactive oxygen species. In silico modelling and molecular approaches suggested that all molecules inhibit XIAP by binding to XIAP-baculoviral IAP repeat domain. This demonstrates a novel aspect of XIAP as a key determinant of tumour control, at the molecular crossroad of caspase-dependent/independent cell death pathway and indicates molecular aspects to develop tumour-effective XIAP antagonists.

New butyrolactone and other metabolites from the bark of Endlicheria arenosa against of the phytopathogen Colletotrichum tamarilloi.

In this work, screening of Lauraceae species for their antifungal activity against Collectotrichum tamarilloi was carried out and the ethanol extract derived from the bark of Endlicheria arenosa was found to be the best candidate. From the ethanolic extract of the bark of E. arenosa, the hexane and chloroform fractions were found to be active, from these five fatty acids were identified and two lactones were isolated. The most active fatty acid was the dodecanoic acid with a minimal inhibitory concentration (MIC) of 78.0 µM. The butyrolactone 3R,4R-licunolide A, it has not previously reported, and licunolide B show both the lowest MIC (55.3 µM). This is the first report of compounds of natural origin as growth inhibitors of C. tamarilloi.

Serotonergic-like profile of 4-propyl-2hbenzo[h]-chromen-2-one (FCS-304) in mice and rats / Perfil de tipo serotoninérgico de 4-propil-2h-benzo[h]-cromen-2-ona (FCS-304) en ratones y ratas

Background: 4-propil-2H-benzo[h]-cromen-2-ona (FCS-304) is a semisynthetic coumarin with MAO-A inhibitory activity and positive results in forced swimming and tail suspension test in mice, but until now, it has not been studied in other screening antidepressant models in mice and rats. Objectives: The aim of this work was to assess the serotonin like effect of FCS-304 in the 5-hydroxytryptophan (5-HTP) test in mice, in the behavioral despair test in rats, and in the reserpine test in rats. Methods: Potentiation of 5-HTP (100 mg/kg, i.p.), induced head twitches were assessed in mice, previously treated with FCS-304 (50-75-150 mg/kg, p.o.). The behavioral despair test was performed in rats treated with FCS-304, recording the immobility time attained by the animals subjected to forced swimming. Antagonism of reserpine-induced ptosis was examined in rats, assessing the level of palpebral closure. Imipramine (30 mg/kg, p.o.) and vehicle (canola oil) served as positive and negative controls, respectively. Results: FCS-304 significantly potentiated 5-HTP induced head twitches in mice, in a dose dependent manner. In rats, FCS-304 significantly decreased the immobility time in the behavioral despair test and antagonized reserpine induced ptosis. Conclusions: These results add support to propose that FCS-304 could elicit antidepressant effects related to MAO-A inhibitory activity.

Antecedentes: 4-propil-2H-benzo[h]-cromen-2-ona (FCS-304) es una cumarina semisintética inhibidora de MAO-A con efectos positivos en las pruebas de nado forzado y suspensión por la cola en ratones, sin embargo, hasta ahora no se había estudiado en otros modelos de tamizado antidepresivo en ratones y ratas. Objetivos: el objetivo de este trabajo fue evaluar el efecto de tipo serotoninérgico de FCS-304 en la prueba de potenciación de 5-hidroxitriptofano (5-HTP) en ratones, y su respuesta en la prueba de desesperanza conductual en ratas y en la prueba de reserpina en ratas. Métodos: se evaluó la potenciación de las sacudidas de cabeza inducidas por 5-HTP (100 mg/kg, i.p.), en ratones tratados con FCS-304 (50-75-150 mg/Kg, v.o.). La prueba de desesperanza conductual se realizó en ratas tratadas con FCS-304, expuestas a nado forzado. El antagonismo de la ptosis palpebral inducida por reserpina se examinó en ratas determinando el grado de apertura ocular. Imipramina (30 mg/kg, v.o.) y el vehículo (aceite de canola, 0,1 mL/10 g), sirvieron como controles positivo y negativo, respectivamente. Resultados: FCS-304 incrementó significativamente el recuento de sacudidas de cabeza inducidas por 5-HTP en ratones, en función de la dosis. En ratas, FCS-304 fue efectiva para disminuir el tiempo de inmovilidad en la prueba de desesperanza inducida por nado forzado y el grado de ptosis palpebral inducido por reserpina. Conclusiones: estos resultados dan soporte para proponer que FCS-304 ejercería efectos de tipo antidepresivo relacionados con la inhibición de MAO-A.

Alcaloides aporfínicos con actividad antituberculosa aislados de Ocotea discolor Kunth (Lauraceae) / Aporphine alkaloids with antitubercular activity isolated from Ocotea discolor Kunth (Lauraceae) / Alcalóides aporfirínicos com atividade antituberculosa isolados de Ocotea discolor Kunth (Lauraceae)

Resumen La tuberculosis causa miles de muertes a nivel mundial y, actualmente, los fármacos usados no son suficientes y en ocasiones son obsoletos para su tratamiento. Por tanto, se hace necesaria la búsqueda de nuevos compuestos que ayuden a combatirla. Se evaluó la actividad antituberculosis de los alcaloides ocoxilonina (1), ocoteina (2), dicentrina (3) y 1,2-metilendioxi-3, 10,11-trimetoxiaporfina (4), aislados de la madera de Ocotea discolor. Las estructuras fueron identificadas por medio del análisis de los datos espectroscópicos de resonancia magnética nuclear (NMR 1D - 1H, 13C, 2D -COSY, HSQC y HMBC), espectros de masas y comparación con datos de la literatura. Todos los compuestos aislados demostraron actividad antituberculosa, con un rango de variación en la concentración mínima inhibitoria entre 140 y 310 μM, siendo la ocoteina (2) la más activa contra la cepa virulenta de Mycobacterium tuberculosis H37Rv.

Abstract Tuberculosis disease causes thousands of deaths worldwide and, currently, the used drugs are either not enough or obsolete for its treatment Therefore, new compounds that combat this disease are been seek Thus, the antituberculosis activity of the alkaloids ocoxilonine (1), ocoteine (2), dicentrine (3) and 1,2-methylenedioxy-3,10,11-trimethoxy aporphine (4), isolated from Ocotea discolor wood was evaluated Their structures were identified by analysis of nuclear magnetic resonance spectroscopic data (NMR 1D - 1H, 13C, 2D - COSY, HSQC and HMBC), mass spectra, and comparison with literature data All the isolated compounds showed antituberculosis activity, with a variation range in the minimum inhibitory concentration between 140 to 310 μM, being ocoteine (2) the most active compound against the virulent strain Mycobacterium tuberculosis H37Rv.

Resumo Devido a que a tuberculose provoca milhares de mortes em todo o mundo e a que, atualmente os medicamentos usados são inadequados e obsoletos para o tratamento desta doença, é preciso buscar novos compostos que ajudem a combatê-la. Assim, foi avaliada a atividade antituberculosis dos alcaloides ocoxilonina (1), ocoteina (2), dicentrina (3) y 1,2-metilendioxi-3,10,11-trimetoxiaporfina (4), isolados a partir da madeira de Ocotea discolor. Estas estruturas foram identificadas pela elucidação dos dados espectroscópicos (NMR 1D - 1H, 13C, 2D -COSY, HSQC e HMBC), espectros de massas e por comparação com os dados da literatura. Todos os compostos isolados demonstraram atividade antituberculosis, com um intervalo de variação na concentração inibitória mínima entre 140 e 310 μM sendo a ocoteína (2) o composto mais ativo contra a variedade virulenta Mycobacterium tuberculosis H37Rv.

Chemical composition and antimicrobial activity of the essential oil of the leaves of ocotea caudata (nees) mez (lauraceae) from Colombia / Composición química y actividad antimicrobiana del aceite esencial de las hojas de ocotea caudata (nees) mez(lauraceae) de Colombia

Ocotea is a genus that belong to Lauraceae family, which has about 56 species, distributed in Asia, Africa and mainly in America. The aim of this work was to identify the chemical composition of the essential oil from leaves of Ocotea caudata collected from Colombia. The chemical composition of the oil was determined by gas chromatography-mass spectrometry (GC-MS), being described for the first time. Thirty nine compounds (corresponding to 92.7 percent of the oil) were identified. The major constituents were germacrene D (55.8 percent), bicyclogermacrene (8.0 percent), beta-caryophyllene (4.6 percent) and beta-bourbonene (2.3 percent). Also the antibacterial activity of the oil was evaluated against two Gram (+) and two Gram (-) bacteria showing that the oil exhibited moderated activity against Gram (+) bacteria.

Resumen: Ocotea es un género perteneciente a la familia Lauraceae, que contiene cerca de 56 especies, distribuidas en Asia, Africa yprincipalmente América. El objetivo de este trabajo fue identificar la composición química del aceite esencial de las hojas de Ocoteacaudata colectadas en Colombia. La composición química del aceite fue determinada por cromatografía de gases–espectrometría de masas(GC-MS), siendo descrita por primera vez. Se identificaron treinta y nueve compuestos (correspondientes al 92.7% del aceite). Loscomponentes mayoritarios fueron germacreno D (55.8%), biciclogermacreno (8.0%), β-cariofileno (4.6%) y β-bourboneno (2.3%). Tambiénse evaluó la actividad antibacteriana del aceite frente a dos bacterias Gram (+) y dos Gram (-) encontrándose que el aceite presentómoderada actividad contra las bacterias Gram (+).

Flavonoid glycosides from Persea caerulea. Unraveling their interactions with SDS-micelles through matrix-assisted DOSY, PGSE, mass spectrometry, and NOESY.

Two flavonoid glycosides derived from rhamnopyranoside (1) and arabinofuranoside (2) have been isolated from leaves of Persea caerulea for the first time. The structures of 1 and 2 have been established by 1 H NMR, 13 C NMR, and IR spectroscopy, together with LC-ESI-TOF and LC-ESI-IT MS spectrometry. From the MS and MS/MS data, the molecular weights of the intact molecules as well as those of quercetin and kaempferol together with their sugar moieties were deduced. The NMR data provided information on the identity of the compounds, as well as the α and ß configurations and the position of the glycosides on quercetin and kaempferol. We have also explored the application of sodium dodecyl sulfate (SDS) normal micelles in binary aqueous solution, at a range of concentrations, to the diffusion resolution of these two glycosides, by the application of matrix-assisted diffusion ordered spectroscopy (DOSY) and pulse field gradient spin echo (PGSE) methodologies, showing that SDS micelles offer a significant resolution which can, in part, be rationalized in terms of differing degrees of hydrophobicity, amphiphilicity, and steric effects. In addition, intra-residue and inter-residue proton-proton distances using nuclear Overhauser effect build-up curves were used to elucidate the conformational preferences of these two flavonoid glycosides when interacting with the micelles. By the combination of both diffusion and nuclear Overhauser spectroscopy techniques, the average location site of kaempferol and quercetin glycosides has been postulated, with the former exhibiting a clear insertion into the interior of the SDS-micelle, whereas the latter is placed closer to the surface. Copyright © 2016 John Wiley & Sons, Ltd.

Seco-limonoid derived from Raputia heptaphylla promotes the control of cutaneous leishmaniasis in hamsters (Mesocricetus auratus).

The rational search of novel bioactive molecules against pathogens with immunomodulatory activity is presently one of the most significant approaches to discover and design new therapeutic agents for effective control of infectious diseases, such as the infection caused by Leishmania parasites. In the present study, we evaluated the therapeutic efficacy of the recently characterized immunomodulatory compound 11α,19ß-dihydroxy-7-acetoxy-7-deoxoichangin, a seco-limonoid derived from the bark of Raputia heptaphylla (Pittier) using: (1) peritoneal macrophages and (2) Mesocricetus auratus hamsters infected with Leishmania (V.) panamensis and Leishmania (L.) amazonensis. We observed the ability of this seco-limonoid to induce the effective control of the parasite either in vitro [determining an effective concentration 50 (EC50) of 59 µ m at the infection model] and in vivo (inducing clinical improvement or even cure in infected animals treated compared with the groups of animals treated with vehicle solution or meglumine antimoniate).

Tetrahydroisoquinolines affect the whole-cell phenotype of Mycobacterium tuberculosis by inhibiting the ATP-dependent MurE ligase.

OBJECTIVES: (S)-Leucoxine, isolated from the Colombian Lauraceae tree Rhodostemonodaphne crenaticupula Madriñan, was found to inhibit the growth of Mycobacterium tuberculosis H37Rv. A biomimetic approach for the chemical synthesis of a wide array of 1-substituted tetrahydroisoquinolines was undertaken with the aim of elucidating a common pharmacophore for these compounds with novel mode(s) of anti-TB action. METHODS: Biomimetic Pictet-Spengler or Bischler-Napieralski synthetic routes were employed followed by an evaluation of the biological activity of the synthesized compounds. RESULTS: In this work, the synthesized tetrahydroisoquinolines were found to inhibit the growth of M. tuberculosis H37Rv and affect its whole-cell phenotype as well as the activity of the ATP-dependent MurE ligase, a key enzyme involved in the early stage of cell wall peptidoglycan biosynthesis. CONCLUSIONS: As the correlation between the MIC and the half-inhibitory enzymatic concentration was not particularly strong, there is a credible possibility that these compounds have pleiotropic mechanism(s) of action in M. tuberculosis.

Anticonvulsant profile of 2-ethylthio-7-methyl-4-(4-methylphenyl)pyrazolo[1, 5-a][1, 3, 5]triazine

This work evaluates the central nervous effects in ICR strain mice of 2-ethylthio-7-methyl-4-(4-methylphenyl)pyrazolo[1,5-a][1,3,5]triazine (MH4b1), a compound obtained by an efficient one-step reaction of S,S-diethyl 4-methylbenzoylimidodithiocarbonate with 5-amino-3-methyl-1H-pyrazole, in order to assess its neuro-pharmacological profile. The tests applied were: maximal electroshock seizure (MES), pentylenetetrazole (PTZ) seizures, forced swimming, plus maze, marble burying, sleeping time, rota-rod and catalepsy. In addition, MH4b1 binding to the benzodiazepine site of the GABA-A receptor and MH4b1 inhibition of monoamine oxidase (MAO) subtypes A and B were evaluated. MH4b1 showed anticonvulsant effects in a dose dependent manner (30-300 mg/kg, p.o.) against MES and inhibition of MAO-B (IC50: 24.5 µM) without activity at the benzodiazepine site. These data suggest that MH4b1 has anticonvulsant properties related to MAO-B inhibition.

Este trabalho avalia o efeito do 2-etiltio-7-metil-4-(4-metilfenil)pirazol[1,5-a][1,3,5]triazina (MH4b1) no sistema nervoso central de camundongos ICR. O MH4b1 foi obtido por a reação de 4-metilbenzoilimidoditiocarbonato de S,S-dietil e 5-amino-3-metil-1H-pirazol em uma única etapa. O perfil neurofarmacológico foi realizado por testes de convulsão induzida por eletrochoque (MES) e pentilenotetrazol (PTZ) e por testes de nado forçado, labirinto em cruz, esconder as esferas, sono barbitúrico, rota-rod e catalepsia. Também foi avaliada a união do MH4b1 ao o local de ligação de benzodiazepínicos do receptor GABA-A e a capacidade inibitória do MH4b1 sobre a monoaminoxidase (MAO) A e B. O MH4b1 mostrou efeito anticonvulsivante dependente da dose (30-300 mg) no teste do MES e apresentou atividade inibitória da MAO-B (CI50: 24.5 µM) sem interagir com o local de ligação de benzodiazepínicos do receptor. Os resultados sugerem que o MH4b1 tem atividade anticonvulsivante relacionada com a inibição da MAO-B.

Assessment of the anticonvulsant activity of pyrazolo[1,5-a][1,3,5]triazines obtained by synthesis / Evaluación de la actividad anticonvulsiva de pirazolo [1,5-a] [1,3,5] triazinas obtenidos por síntesis

Giving that the pyrazolo[1,5-a][1,3,5]triazine system is a potential source of pharmacological agents for treatment of central nervous system disorders this work was aimed to asses anticonvulsant and acute neurotoxic effects of six molecules obtained by synthesis, using experimental models in mice. A series of six pyrazolo[1,5-a][1,3,5]triazines (EAC-21, EAC-31, EAC-33, MH4a, MH4b1 and MH4c) obtained by one-step reaction from S,S-diethyl aroyl-/hetaroylimidodithiocarbonates and 5-aminopyrazoles were screened in vivo (300 mg/kg, v.o.) for their anticonvulsant activity in the maximal electroshock (MES) test in ICR mice and for acute toxicity in the rota-rod and wiring test. The structures of the obtained compounds were unambiguously established by IR, 1H and 13C-NMR spectroscopic techniques, COSY 1H-1H, HSQC and HMBC experiments, mass spectrometry and elemental analyses. Results shown that only MH4b1 showed protection against MES (p<0.05) and was devoid of gross neurotoxicity signs. Therefore, MH4b1 was chosen for additional anticonvulsant screening against MES, pentilenetetrazole, picrotoxin, strychnine and 6 Hz psychomotor seizure model, in a dose dependent manner (50, 150, 300 mg/kg, v.o.). MH4b1 also protected against 6 Hz seizure test (>150 mg/kg, v.o.). These data suggest that MH4b1 could be a source for anticonvulsant pyrazolo[1,5-a][1,3,5]triazine analogs potentially useful against tonic clonic and refractory seizures.

Dado el interés que el sistema pirazolo[1,5-a][1,3,5]triazina tiene como fuente potencial para la obtención de agentes farmacológicos para el tratamiento de trastornos del sistema nervioso central, en este trabajo se efectuó el cribado anticonvulsivante y el efecto neurotóxico agudo de seis moléculas derivadas de este sistema, en ratones ICR. La serie de compuestos denominados EAC-21, EAC-31, EAC-33, MH4a, MH4b1 y MH4c, obtenidas por la reacción de S,S-dietil aroil-/heteroilimidoditiocarbonatos y 5-aminopirazoles se evaluó in vivo (300 mg/kg, v.o.) en la prueba de convulsiones inducidas por electrochoque y en las pruebas de actividad neurotóxica aguda del eje rodante y del alambre. La estructura de estos compuestos se determinó por técnicas de infrarrojo, espectroscopia de 1H, 13C-NMR, COSY 1H-1H, experimentos de HSQC y HMBC, espectrometría de masas y análisis elemental. Los resultados mostraron que el compuesto MH4b1 confirió protección frente a las convulsiones inducidas por electrochoque (p<0.05) sin producir signos de neurotoxicidad aguda. Por consiguiente, MH4b1 se escogió para las siguientes pruebas de actividad anticonvulsivante, dosis - respuesta (50, 150, 300 mg/kg, v.o.): electrochoque, pentilenetetrazol, picrotoxin, estricnina y el modelo de convulsión psicomotora de 6 Hz. MH4b1 mostró efectos protectores en función de la dosis frente a las pruebas de convulsión por electrochoque (>150 mg/kg) y convulsión de 6 Hz (300 mg/kg, v.o.). Estos resultados sugieren que MH4b1 podría constituirse en fuente anticonvulsivante del sistema pirazolo[1,5-a][1,3,5]triazina eventualmente útil para el tratamiento de las crisis tónicas clónicas generalizadas y las crisis refractarias.

Croton schiedeanus Schltd prevents experimental hypertension in rats induced by nitric oxide deficit

Croton schiedeanus Schltd (N.V.: "almizclillo") is a plant used in traditional medicine as an antihypertensive in Colombia. It contains flavonoid, diterpenoid and fenilbutanoid metabolites that have vasodilatation effects linked to the NO/cGMP pathway. This work aimed to assess the capacity of a 96% EtOH extract to prevent the hypertension induced by nitric oxide (NO) deficiency in rats. The NO synthase inhibitor L-NAME (10 mg/kg/d, i.p) was administered during five weeks to three groups of rats (6-7 animals): C. Schiedeanus (200 mg/kg/d, p.o), enalapril (reference, 10 mg/kg/d, p.o) and vehicle (control: olive oil 1 ml/kg/d, p.o). In addition, the blank group received only vehicle. The arterial blood pressure (BP) and heart rate (HR) were measured daily for six weeks. After sacrificing the animals, the aortic rings were isolated, contraction was triggered with phenylephrine (PE 10-6 M) and relaxant responses were achieved with cumulative concentrations of acetylcholine (ACh, 10-10 - 10-4 M). L-NAME increased the systolic arterial pressure in the control group, attaining mean values of 131 mm Hg at week 5, whereas the C. schiedeanus, enalapril and blank groups maintained blood pressure under 100 mm Hg. The capacity of PE to contract aortic rings was greater in the C. schiedeanus, enalapril and blank groups than in the control group (2157, 2005, 1910 and 1646 mg, respectively). The pEC50 values for ACh were as follows: C. Schiedeanus (6.89) >enalapril (6.39) > blank (5.68) > control (5.09). These results give support to C. Schiedeanus as a natural antihypertensive source.

Croton schiedeanus Schltd (NV: "almizclillo") é utilizado na medicina tradicional da Colômbia para o tratamento da hipertensão arterial. Outras pesquisas demonstraram que a planta tem metabólitos como os flavonoides, os diterpenoides e os fenilbutanoides, os quais têm comprovados efeitos vasodilatadores vinculados com a via NO/GMPc. O objetivo deste estudo foi avaliar a capacidade do extrato de Croton schiedeanus Schltd em EtOH a 96% na prevenção da hipertensão induzida pela deficiência de óxido nítrico (NO), em ratos. O inibidor da NO sintetase L-NAME (10 mg/kg/d, ip) foi administrado durante cinco semanas em três grupos de ratos (6-7 animais): C. schiedeanus (200 mg/kg/d, v.o.), enalapril (referência, 10 mg/kg/d, v.o.) e o veículo (controle: azeite de oliva 1 mL/kg/d, v.o.). O grupo branco recebeu somente o veículo. A pressão sanguínea (BP) e a frequência cardíaca (FC) foram medidas diariamente em um período de seis semanas. Após o sacrifício, os anéis aórticos foram isolados e contraídos, utilizando fenilefrina (PE 10-6 M) e as respostas para a relaxação foram obtidas com doses acumulativas de acetilcolina (ACh, 10-10-10-4 M). Os resultados demonstraram que o L-NAME provocou incremento significativo da pressão nos ratos do grupo controle, obtendo-se valores médios de 131 mm Hg na quinta semana. No entanto, os grupos C. schiedeanus, enalapril e branco mantiveram a pressão arterial aos níveis médios iniciais 100 mm Hg. A capacidade da PE para fazer a contração dos anéis da aorta foi maior nos grupos C. schiedeanus, enalapril e branco do que no grupo controle (2157, 2005, 1910 and 1646 mg, respectivamente). Os valores de pCE50 de ACh foram os seguintes: C. schiedeanus (6,89) > enalapril (6,39) > branco (5,68) > controle (5,09). Pode-se afirmar que estes resultados dão suporte à C. schiedeanus como fonte natural anti-hipertensiva.

Efecto citotóxico de algunos compuestos naturales aislados de plantas Laureaceae y derivados sintéticos / Cytotoxic effect of some natural compounds isolated from Lauraceae plants and synthetic derivatives

Introducción. El efecto contra la proliferación celular de once neolignanos, dos lignanos y un diterpeno, aislados de tres plantas de la familia Lauraceae, y cuatro benzofuranos y dos biciclooctanos sintéticos, fue evaluado in vitro sobre cinco líneas celulares derivadas de tumores sólidos de alta incidencia en Colombia.Objetivo. Evaluar el efecto citotóxico de veinte compuestos sobre las líneas tumorales HeLa, A-549, Hep-2, PC-3 y MCF-7. Materiales y métodos. Los 14 compuestos de origen natural fueron aislados de tres plantas nativas colombianas (Pleurothyrium cinereum, Ocotea macrophylla y Nectandra amazonum) por técnicas cromatográficas y se establecieron sus estructuras por métodos espectroscópicos, y los seis derivados sintéticos fueron preparados mediante reacción de oxiarilación y metilación con diazometano. El efecto contra la proliferación y la recuperación celular se hicieron mediante tratamiento in vitro de las líneas tumorales con los compuestos , evaluando la viabilidad celular por tinción con resazurina.Resultados. Entre los compuestos evaluados, solamente ocofilal A, cinerina D, ácido kaurenoico, dos benzofuranos y la (-)-cinerina A sintética presentaron actividad contra la proliferación celular en diferentes niveles. Los biciclooctanos, así como el ácido kaurenoico, fueron activos contra todas las líneas celulares, mientras que los benzofuranoides mostraron actividad selectiva contra HeLa. Además, la (-)-cinerina A exhibió un efecto letal total contra todas las líneas celulares, mientras que el ácido kaurenóico presentó efecto letal total contra PC-3, Hep-2 y A549.Conclusión. Los compuestos evaluados que exhibieron actividad contra la proliferación celular mostraron resultados interesantes, lo cual sugiere su potencial uso como cabezas de serie o moléculas plantilla en el desarrollo de agentes anticancerígenos.

Introduction. The antiproliferative effect of eleven neolignans, two lignans and one diterpene isolated from three Lauraceae plants, four benzofurans and two bicyclooctanes synthetic derivatives was evaluated in vitro on a set of five human cancer cells from solid tumors with a high incidence in Colombia.Objective. To evaluate the cytotoxic effect of twenty compounds on the tumor cell lines HeLa, A-549, Hep-2, PC-3, and MCF-7.Materials and methods. Fourteen natural compounds were isolated by chromatographic techniques from three native colombian plants (Pleurothyrium cinereum, Ocotea macrophylla and Nectandra amazonum), whose structures were established by spectroscopic methods; six synthetic derivatives were prepared by oxyarylation and diazomethane methylation. Antiproliferative effect and cell recovery were performed by means of in vitro treatment of tumor cell lines with test compounds, evaluating cell viability by resazurin staining.Results. Among test compounds, only neolignans ocophyllal A, cinerin D, kaurenoic acid, two benzofuran-derivatives, and synthetic (-)-cinerin A were found to have antiproliferative effect at different levels. Bicyclooctanoids as well as kaurenoic acid exhibited activity against all human cancer cells while benzofuranoids showed selective activity against HeLa. Furthermore, compounds (-)-cinerin A and kaurenoic acid exhibited total lethal effect against all-five cell lines and PC-3, Hep-2, and A549 cell lines, respectively.Conclusion. Test compounds exhibiting antiproliferative activity showed interesting results, which would promote their use as lead compounds on further studies for anticancer agents development.

FLAVONOIDES CON ACTIVIDAD ANTIFÚNGICA AISLADOS DE Piper septuplinervium (Miq.) C. DC. (Piperaceae) / ANTIFUNGAL FLAVONOIDS ISOLATED FROM Piper septuplinervium (Miq.) C. DC (Piperaceae) / FLAVONÓIDES COM ATIVIDADE ANTIFÚNGICA ISOLADOS DE Piper septuplinervium (Miq.) C. DC (Piperaceae)

El fraccionamiento bioguiado del extracto etanólico de la parte aérea de Piper septuplinervium (Piperaceae) permitió la obtención de dos substancias de tipo flavonoide, activas contra dos cepas de hongos fitopatógenos (Fusarium oxysporum f. sp. dianthiyBotrytis cinerea). Las estructuras de los compuestos aislados fueron determinadas de acuerdo con el análisis espectroscópico (RMN uni y bidimensional, EMAR). La actividad anti-fúngica fue determinada por ensayo en disco, seguido por bioautografía directa sobre las dos cepas de hongos en prueba.

Guided fractionation of ethanolic extract of aerial part of Piper septuplinervium (Piperaceae) yielded two flavonoid-type active substances against two strains of phytopathogenic fungi (Fusarium oxysporum f. sp. dianthi and Botrytis cinerea). The structures of isolated compounds were determined by spectroscopic analysis (single-and two-dimensional NMR, HRMS). The antifungal activity was determined by disk test, followed by direct bioautography against the two strains of fungi tested.

O fracionamento bio-guiado do extrato etanólico da parte aérea de Piper septuplinervium (Piperaceae) permitiuobter duas substâncias flavonóidesativas contra duas linhagens de fungos patogênicos (Fusarium oxysporum f. sp. Dianthi e Botrytis cinerea). Mediante a análise espectroscópica (RMN mono e bidimensional, RMS) determinaram-se as estruturas desses compostos. A atividade antifúngica foi determinada pelo teste de disco, seguido por bio-autografia direta sobre duas inhagens fúngicas testadas.

Leishmanicidal and cytotoxic activities of extracts and naturally-occurring compounds from two Lauraceae species.

The in vitro leishmanicidal effects of ethanolic extracts and fifteen naturally-occurring compounds (five lignans, eight neolignans, a diterpene and a dihydrochalcone), obtained from Pleurothyrium cinereum and Ocotea macrophylla, were evaluated on promastigotes of Leishmania panamensis and L. braziliensis. In addition, in order to determine the selective action on Leishmania species as a safety principle, in vitro cytotoxicity on J774 cells was also evaluated for test compounds and extracts. One extract and seven compounds showed activity against Leishmania parasites at different levels. Dihydroflavokawin B (8) was found to be the most potent antileishmanial compound on both parasites, whilst (+)-otobaphenol (14), was found to be the most selective compound on L. panamensis.

Cytotoxic effect of some natural compounds isolated from Lauraceae plants and synthetic derivatives.

INTRODUCTION: The antiproliferative effect of eleven neolignans, two lignans and one diterpene isolated from three Lauraceae plants, four benzofurans and two bicyclooctanes synthetic derivatives was evaluated in vitro on a set of five human cancer cells from solid tumors with a high incidence in Colombia. OBJECTIVE: To evaluate the cytotoxic effect of twenty compounds on the tumor cell lines HeLa, A-549, Hep-2, PC-3, and MCF-7. MATERIALS AND METHODS. Fourteen natural compounds were isolated by chromatographic techniques from three native Colombian plants (Pleurothyrium cinereum, Ocotea macrophylla and Nectandra amazonum), whose structures were established by spectroscopic methods; six synthetic derivatives were prepared by oxyarylation and diazomethane methylation. Antiproliferative effect and cell recovery were performed by means of in vitro treatment of tumor cell lines with test compounds, evaluating cell viability by resazurin staining. RESULTS: Among test compounds, only neolignans ocophyllal A, cinerin D, kaurenoic acid, two benzofuran-derivatives, and synthetic (-)-cinerin A were found to have antiproliferative effect at different levels. Bicyclooctanoids as well as kaurenoic acid exhibited activity against all human cancer cells while benzofuranoids showed selective activity against HeLa. Furthermore, compounds (-)-cinerin A and kaurenoic acid exhibited total lethal effect against all-five cell lines and PC-3, Hep-2, and A549 cell lines, respectively. CONCLUSION: Test compounds exhibiting antiproliferative activity showed interesting results, which would promote their use as lead compounds on further studies for anticancer agents development.

NOVEL FUROCARBAZOLE A LKALOIDS AND ANTIBACTERIAL ACTIVITY OF ETHANOL EXTRACT FROM Zanthoxylum fagara (L.) Sargent / NUEVOS ALCALOIDES FUROCARBAZÓLICOS Y ACTIVIDAD ANTIBACTERIANA DEL EXTRACTO ETANÓLICO DE Zanthoxylum fagara (L.) Sargent / NOVOS ALCALÓIDES FUROCARBAZÓLICOS E ATIVIDADE ANTIBACTERIANA DO EXTRATO ETANÓLICO DE Zanthoxylum fagara (L.) Sargent

From ethanol-soluble extract of the bark from Zanthoxylum fagara (L.) Sargent. were isolated two novel furocarbazole alkaloids, 4-methoxy-10ff-furo[3,2-a]car-bazole (1) and 10ff-furo[3,2-a]carbazole (2), whose structures were elucidated on the basis of IR, MS and NMR (including 1D and 2D) techniques. In addition, the antibacterial effect of the ethanol extract of bark was evaluated against Gram-negative bacteria Escherichia coli, Salmonella typhi, Shigella boydii, Vibrio chole-rae El Tor, and Vibrio cholerae clinical lysate; and Gram-positive bacteria Bacillus subtilis and Staphylococcus epidermidis, using the Agar-well diffusion method. In above-mentioned assay was found that the ethanol extract of bark exhibited inhibition against strains B. subti-lis (17mm), V. cholerae El Tor (11mm), V. cholerae clinical lysate (10mm), and S. epidermidis (9mm).

Del extracto etanólico de corteza de Zanthoxylum fagara (L.) Sargent se aislaron dos nuevos alcaloides de núcleo furocarbazólicos, 4-metoxi-10H-furo[3,2-a]carbazol (l)y10ff-furo[3,2-a]carbazol (2), cuyas estructuras fueron elucidadas utilizando técnicas de IR, EM y RMN (en una y dos dimensiones). Con el extracto etanólico de corteza se realizaron ensayos de actividad biológica antibacteriana con las cepas gram-negativas Escherichia coli, Salmonella typhi, Shigella boydii, Vibrio cholerae El Tor, Vibrio cholerae caso clínico; y gram-positivas Bacillus subtilis,y Staphylococcus epidermidis, utilizando el método de difusión en agar. En este ensayo se encontró que el extracto etanólico de corteza presentó inhibición para las cepas de B. subtilis (17 mm), V. cholerae El Tor (11 mm), V. cholerae caso clínico (10 mm) y S. epidermidis (9 mm).

O extrato etanólico da casca de Zanthoxylum fagara (L.) Sargent. foram isolados dois novos alcalóides furocarbazolicos, 4-metoxi-10H-furo[3,2-a]carbazol (l)e10ff-furo [3,2-a]carbazol (2), cujas estruturas foram elucidados usando técnicas de IR, EM e RMN (em uma e duas dimensões). Com o extrato etanólico da casca foi testada atividade biológica antibacteriana com Gram-negativas estirpes Escherichia coli, Salmonella typhi, Shigella boydii, Vibrio cholerae El Tor, Vibrio cholerae caso clínico; e Gram-positivas Bacillus subtilis e Staphylococcus epidermidis, utilizando o método de difusão em ágar. Neste ensaio foi encontrado que o extrato etanólico da casca apresentou inibição para as estirpes de B. subtilis (17mm), V. cholerae El Tor (11mm), V. cholerae caso clínico (10mm) e S. epidermidis (9mm).