Antileishmanial Effect of 5,3'-Hydroxy-7,4'-dimethoxyflavanone of Picramnia gracilis Tul. (Picramniaceae) Fruit: In Vitro and In Vivo Studies.

Species of Picramnia genus are used in folk medicine to treat or prevent skin disorders, but only few species have been studied for biological activity and chemical composition. P. gracilis Tul. is a native species from Central and South America and although its fruits are edible, phytochemical analysis or medicinal uses of this species are not known. In the search of candidates to antileishmanial drugs, this work aimed to evaluate the antileishmanial activity of P. gracilis Tul. in in vitro and in vivo studies. Only ethanolic extract of fruits showed leishmanicidal activity. The majoritarian metabolite was 5,3'-hydroxy-7,4'-dimethoxyflavanone ether that exhibited high activity against L. (V.) panamensis (EC50 17.0 + 2.8 mg/mL, 53.7 µM) and low toxicity on mammalian U-937 cells, with an index of selectivity >11.8. In vivo studies showed that the flavanone administered in solution (2 mg/kg/day) or cream (2%) induces clinical improvement and no toxicity in hamsters with CL. In conclusion, this is the first report about isolation of 5,3'-hydroxy-7,4'-dimethoxyflavanone of P. gracilis Tul. The leishmanicidal activity attributed to this flavanone is also reported for the first time. Finally, the in vitro and in vivo leishmanicidal activity reported here for 5,3'-hydroxy-7,4'-dimethoxyflavanone offers a greater prospect towards antileishmanial drug discovery and development.

Synthesis and attioxidant activity of two isoespintanol derivatives / Síntesis y ativiidad antioxidante de dos derivados de isoespintaoll / Síntese eatividaade antioxidante dos derivados do isoespintanol

The antioxidant activity of isoespintanol (1) hemisynthetic analogues, 4-bromo-2-isopropyl-3,6-dimethoxy-5-methylphe-nol (2) and 3-isopropyl-6-methylbenzene-1,2,4-triol (3), was evaluated using ABTS, DPPH and FRAP assays. Partial rationalization of the results is provided in terms of quantum chemical calculations of bond dissociation enthalpy (BDE) and ionization potential (IP).

La actividad antioxidante de los análogos hemisintéticos del isoespintanol (1), 4-bromo-2-isopropil-3,6-dimetoxi-5-metil-fenol (2) y 3-isopropil-6-metilbenceno-1,2,4-triol (3), se evaluó empleando los ensayos ABTS, DPPH y FRAP. La racionalización de los resultados es provista de forma parcial en términos de cálculos cuánticos de entalpia de disociación de enlace (BDE) y potencial de ionización (IP).

A atividade antioxidante dos análogos hemi-sintéticos de isoespintanol (1), 4-bromo-2-isopropil-3,6-dimetoxi-Smetilfenol (2) e 3-isopropil-6metilbenze-no- 1,2,4-triol (3 foi avahada através das técnicas de ABTS, DPPH e FRAP A racionalizagáo dos resultados está prevista, em parte, em termos de cálculos quánticos de entalpia de dissociagáo da ligagáo (BDE) e potencial de ionizagáo (IP).

Coumarins from Galipea panamensis and Their Activity against Leishmania panamensis.

Two new coumarin compounds (1 and 2), phebalosin (3), its derived artifact murralongin (4), and murrangatin acetonide (5) were isolated from the leaves of Galipea panamensis. The structures of 1 and 2 were assigned as 7-{[(2R*)-3,3-dimethyloxiran-2-yl]methoxy}-8-[(2R*,3R*)-3-isopropenyloxiran-2-yl]-2H-chromen-2-one and 7-methoxy-8-(4-methyl-3-furyl)-2H-chromen-2-one, respectively, on the basis of their spectroscopic data (primarily NMR and MS). Compounds 1-3 were tested against axenic amastigote forms of Leishmania panamensis and displayed 50% effective concentrations (EC(50)) of 9.9, 10.5, and 14.1 microg/mL, respectively. These three compounds also displayed cytotoxicity (IC(50)) at concentrations of 9.7, 33.0, and 20.7 microg/mL, respectively, on human promonocytic U-937 cells.

Effect of Solanum nudum steroids on uninfected and Plasmodium falciparum-infected erythrocytes.

Steroids from Solanum nudum (SNs) have demonstrated antiplasmodial activity against erythrocytic stages of the Plasmodium falciparum strain FCB-2. It is well known that steroids can alter the membrane function of erythrocytes. Thus, we assessed alterations in the membranes of uninfected red blood cells, the parasite invasiveness and the solute-induced lysis of parasitised red blood cells (pRBCs). induced by SNs. We found that most merozoites were unable to invade SN-treated erythrocytes. However, transmission electron microscopy revealed no effect on the morphology of uninfected erythrocytes treated with either SN2 or diosgenone and neither SN induced haemolysis of uninfected erythrocytes. SN2 and SN4 inhibited isosmotic sorbitol and alanine-induced haemolysis of pRBCs. In contrast, diosgenone and SN1 did not inhibit solute-induced haemolysis. The inhibition of solute-induced lysis of parasitised erythrocytes by SN2 and SN4 suggest an action of these SNs on new permeability pathways of pRBCs.

Structure-activity relationship in the interaction of substituted perinaphthenones with Mycosphaerella fijiensis.

The levels of native fungitoxic perinaphthenone phytoalexins in susceptible Musa varieties (banana), which are commercially grown in large plantations, are too low to provide plants with long-lasting protection against highly pathogenic fungi. Novel strategies for plant protection are necessary to reduce crop losses and to prevent the development of resistant fungal strains. The synthesis of novel fungicides based on the structures of perinaphthenone natural products is considered to be a promising strategy. Thirteen substituted perinaphthenones, among them two known natural products (1, 2) and 11 synthetics (3-13), were evaluated for their activity against Mycosphaerella fijiensis , and their half-maximal inhibitory concentrations (IC(50)) were calculated to establish structure-activity relationships (SAR). A SAR trend was hypothesized, leading to the design of a new compound, 4-methoxy-2-nitro-1H-phenalen-1-one (14); the new compound displayed significantly enhanced in vitro activity against M. fijiensis compared to other perinaphthenone derivatives. The activity of 14 was comparable to that of two commercial fungicides.

Plasmodium falciparum: effect of Solanum nudum steroids on thiol contents and beta-hematin formation in parasitized erythrocytes.

We studied the effects on total thiols glutathione (GSH) and cysteine contents in Plasmodium falciparum in vitro when treated with four steroid derivatives and a sapogenin (Diosgenone) extracted from Solanum nudum. We also determined their capacity to inhibit beta-hematin formation. We showed that SN-1 (16alpha-acetoxy-26-hydroxycholest-4-ene-3,22-dione) increased total glutathione and cysteine concentrations while SN-4 (26-O-beta-d-glucopyranosyloxy-16alpha-acetoxycholest-4-ene-3,22-dione) decreased the concentration of both thiols. Acetylation in C16 was crucial for the effect of SN-1 while type furostanol and terminal glucosidation were necessary for the inhibitory properties of SN-4. The combination of steroids and buthionine sulfoximine, a specific inhibitor of a step-limiting enzyme in GSH synthesis, did not modify the glutathione contents. Finally, we found that SN-1 inhibited more than 80% of beta-hematin formation at 5.0mM, while the other steroids did not show any effect.

Anti-inflammatory activity of berenjenol and related compounds.

Berenjenol (1), isolated from Oxandra cf. xylopioides (Annonaceae), was tested on two different experimental models of inflammation. The compound showed anti-inflammatory activity in the test of acute mouse ear edema induced by TPA (54% inhibition, 1 micromol/ear) as well as in the test of subchronic inflammation induced by repeated application of TPA (57% inhibition, 7x1 micromol/ear). Moreover, while it reduced the expression of both COX-2 (65% inhibition at 50 microM) and iNOS (80% inhibition at 50 microM), it was not active against TNF-alpha and IL-1 beta in murine macrophages (RAW 264.7) stimulated with LPS. Structural modification of 1 gave two derivatives, berenjenol acetate (2) and 3-oxo-berenjenol (3). Of these, the latter had a high degree of activity in the acute test (66% inhibition, 1.1 micromol/ear), whereas the former showed no enhanced pharmacological properties. Interestingly, the original compound exhibited higher activity than either of its derivatives in the subchronic model. We thus concluded that whereas 3-oxidation of 1 (compound 3), but not 3-acetylation (2), increases the activity in the acute model of inflammation, structural modification of 1 does not enhance the compound's effects in the subchronic model.

Determinación d la actividad antioxidante en u modelo de peroxidación lipídicca de mantequilla inhibida por el isoespintanol / Anioxidant activvity determinationin a lipidic peroxidation modell of butter inhibited by isoespintanol

En este trabajo se evalúa la actividad antioxidante (Φ), definida como la pendiente de la regresión simple lineal de f o /f i contra la concentración µM, en un modelo de inhibición de la peroxidación lipídica de mantequilla a 60ºC, donde fi es el efecto de cada concentración del isoespintanol y fo es el control. Se encuentra que la formación de hidroperóxidos (valor de peróxido PV) y las especies mas oxidadas reactivas al ácido tiobarbiturico (TBARS) fueron retardadas de manera similar por el isoespintanol (ΦTBARS=9.46x10-5 ± 1.33x10-5 y ΦPV = 9.41x10-5 ± 1.62x10-5). De igual manera, el butilhidroxi tolueno y el isoespintanol inhiben el proceso oxidativo de mantequilla en un 28.0 y 23.3 % a concentraciones de 2380.9 y 3809.5 µM respectivamente.

The antioxidant activity (Φ) is defined as the slope of the simple linear regression of f0/f i against the concentration µM, in an inhibition model of lipid peroxidation of butter at 60° C, where f i is the concentration effect of isoespintanol and f0 is the control. It is found that the formation of: hydroperoxides (peroxide value of PV) and the most oxidized species reactive to thiobarbituric acid (TBARS), were similarly delayed by isoespintanol (ΦTBARS = 9.46x10-5 ± 1.33x10-5 and ΦPV = 9.41x10-5 ± 1.62x10-5). Likewise, the butilhidroxy toluene and isoespintanol inhibit the oxidative process of butter in a 28.0 and 23.3% at concentrations of 2380.9 and 3809.5 µ M respectively.

Actividad antioxidante del isoespintanol en diferentes medios / Antioxidant activity of Isoespintanol in different media

Se midió la actividad antioxidante del isoespintanol (2-Isopropil-3,6-dimetoxi-5-metilfenol), aislado de las hojas Oxandra cf xylopiodes, en diferentes modelos. Los resultados indican que el isoespintanol es un mejor reductor que el BHT en el ensayo FRAP. En los sistemas emulsificados decoloacion de B-caroteno y peroxidación lipídica inducida por Fe/ascorbato y en el ensayo cinético de DPPH, el isoespintanol y BHT tienen comportamientos antioxidantes similares. El BHT es un mejor atrapador de los radicales libres DPHH y ABTS. Isoespintanoly BHT no atrapan el radical superóxido y no inhiben significativamente la xantina oxidasa

Semisynthetic roxburghin tetra-methyl ether.

The title mol-ecule, (E)-2,3',4,5-tetra-methoxy-stilbene, C(18)H(20)O(4), is virtually planar. The angle between the two benzene rings is 4.06 (6)°. The inter-molecular inter-actions present in the structure are weak. There are C-H⋯O hydrogen bonds and C-H⋯π-electron ring inter-actions. The mol-ecules are ordered into planes that are parallel to (01). The distance between adjacent planes is about 3.3 Šand therefore π-π electron inter-actions between the aromatic planes are also plausible.

New antitumoral acetogenin 'Guanacone type' derivatives: isolation and bioactivity. Molecular dynamics simulation of diacetyl-guanacone.

We describe herein the isolation and semisynthesis of four acetogenin derivatives (1-4) as well as their ability to inhibit the mitochondrial respiratory chain and several tumor cell lines. In addition, four nanoseconds (ns) of MD simulation of compound 4, in a fully hydrated POPC bilayer, is reported.

Constituents of Oxandra cf. xylopioides with anti-inflammatory activity.

A new triterpenoid (1) derived from 24-methylcycloartanol was isolated from the leaves of Oxandra cf. xylopioides. An unusual structure of the new compound was assigned as 1, for which the name berenjenol is proposed, on the basis of the spectroscopic data of the natural product and of its derivatives 2 and 3. The leaves also afforded the known monoterpene isoespintanol (4). Compounds 1 and 4 significantly reduced the paw edema induced by carrageenan by 64% and 43%, at 3 h, respectively. Moreover, 4 reduced IL-1 beta production by 72% at 100 microM and reduced IL-1 beta mRNA synthesis.

Prevention of sporogony of Plasmodium vivax in Anopheles albimanus by steroids of Solanum nudum Dunal (Solanaceae).

The sporontocidal activity of three steroids (SN-1, SN-2 and SN-4) from Solanum nudum Dunal (Solanaceae) was determined against naturally circulating isolates of Plasmodium vivax in Anopheles albimanus. Laboratory-reared Anopheles albimanus mosquitoes were infected with P. vivax from gametocytemic blood of volunteers resident in Buenaventura, Valle del Cauca (Colombian Pacific Coast) by using an artificial membrane feeder. Prior to mosquito feeding, gametocytemic blood was centrifuged, plasma was separated, packed blood red cells were washed with RPMI 1640 and then resuspended in non-immune AB serum, then the steroids were added at different doses. On day 7 after infection, the presence and number of oocysts in mosquitoes was determined. The steroid SN-2 reduced the infection of mosquitoes by 90% and the mean number of oocysts by 60%. These data confirmed that the experimental steroid is capable of interrupting the sporogonic development of P. vivax in Anopheles albimanus. This experimental steroid has potential for transmission blocking in vivax malaria.

Effect of Solanum nudum Dunal (Solanaceae) steroids on hepatic trophozoites of Plasmodium vivax.

Steroids isolated from the plant Solanum nudum showed antiplasmodial activity against the blood stages of Plasmodium falciparum. It has been demonstrated that these steroids are neither mutagenic in vitro nor clastogenic in vivo. This study evaluated the effect of five steroids of S. nudum (SN-1, SN-2, SN-3, SN-4 and SN-5) on hepatic trophozoites of P. vivax, using an experimental design, non-balanced, with blind determination of the effect expressed as the percentage reduction of hepatic trophozoites. The sporozoites used to inoculate human hepatoma cells HepG2-A16 were obtained from gametocytemic blood of volunteers infected only with P. vivax, and passed into laboratory-reared Anopheles albimanus mosquitoes. Steroids were added at three different doses (100, 10 and 1 microg/mL) just after inoculation of the cells with sporozoites. The effect was determined by indirect immunofluorescence assays using the monoclonal antibodies Pv210 or Pv47E-2E10 and steroid cytotoxicity on HepG2-A16 cells was assessed by the MTT method. All the steroids reduced the number of hepatic P. vivax trophozoites, SN-2 and SN-4 reduced the number of hepatic trophozoites by 47% and 39% (p < 0.05), respectively.

Guanaconetins, new antitumoral acetogenins, mitochondrial complex I and tumor cell growth inhibitors.

The antitumoral activity of a series of acetylated bis-tetrahydrofuranic acetogenins with a threo/trans/threo/trans/erythro relative configuration was characterized by four new natural and two semisynthetic, 15,24,30-trioxygenated acetogenins that were found to inhibit mitochondrial complex I enzyme as well as growth of several tumor cell lines. Placement of acetyl groups along the alkyl chain modulated the potency of the bis-tetrahydrofuranic acetogenins and could be important for future utilization of these compounds as chemotherapeutic agents.

Antiprotozoal 6-substituted-5,6-dihydro-alpha-pyrones from Raimondia cf. monoica.

Dichloromethane extracts of both the roots and the leaves of Raimondia cf. monoica showed in vitro antiplasmodial and leishmanicidal activities against Plasmodium falciparum and Leishmania panamensis, respectively. Three 6-substituted 5,6-dihydro-2H-pyran-2-ones were isolated. (1) and (2) were identified as (6S)-(5'-oxohepten-1'E,3'E-dienyl)-5,6-dihydro-2H-pyran-2-one (1) and (6R)-(5'-oxohepten-1'Z,3'E-dienyl)-5,6-dihydro-2H-pyran-2-one (2), respectively. (-)-Arentilactone (3) was also isolated. The structure of the new compound (1) was determined by spectroscopic methods; additional spectroscopic data for (2) are reported for the first time.

Volátiles de una reacción de éter de petróleo de la corteza de raimondia CF. Monoica (ANNONACEAE) / A volatile petroleum ether fraction from the crust of raimondia CF Monoica (ANNONACEAE)

Los componentes volátiles de la corteza de Raimondiacf. monoica fueron aislados por extracción con éter Catorce compuestos se identificaron cuyos componentes mayoritarios son a-humuleno, b-farneseno, b-elemeno y cariofileno. El porcentaje de aceite contenido en la corteza fue del 2.7 por ciento

Two Highly Populated Conformations at Room Temperature of Monterine and Granjine, Antitumor Bisbenzylisoquinoline Alkaloids: Origin and Tridimensional Structures.

Monterine 1 as well as granjine 3, 1R,1'S configured biphenylic bisbenzylisoquinoline alkaloids, generate two highly populated conformers. The interconversion of two forms was detected by saturation tranfer in (1)H NMR NOEs experiments. Tridimensional structure of the conformers was determined on the basis of (1)H NMR analysis of anisotropic shielding protons, by NOEs measurements and vicinal proton coupling constants of CH1-CH(2)alpha and CH1'-CH(2)alpha'. The structures established from NMR data were further refined to observe the mobility of 3D conformations by molecular dynamics simulation in vacuo. The highly populated conformers, monterine 1a and 1b, as well as granjine 3a and 3b, are interconvertible by rotation about the C1'-Calpha', Calpha'-C9', and C11'-C11 bonds and inversion of the benzyl D ring by reference to CH(2)alpha'. The slow exchange system was investigated by dynamic NMR spectroscopy: DeltaG()(c) 77.9 KJ/mol and k(c) 200 s(-)(1) for monterine 1; DeltaG()(c) 77.7 KJ/mol and k(c) 211 s(-)(1) for granjine 3. Natural and synthetic biphenylic bisbenzylisoquinolines displayed, in vitro, cytotoxic activities against human prostate and breast cancer cell lines.