Flavonoids from Piper Species as Promising Antiprotozoal Agents against Giardia intestinalis. Structure-Activity Relationship and Drug-Likeness Studies.

Diarrhea diseases caused by the intestinal protozoan parasite Giardia intestinalis are a major global health burden. Moreover, there is an ongoing need for novel anti-Giardia drugs due to drawbacks with currently available treatments. This paper reports on the isolation and structural elucidation of six new flavonoids (1-6), along with twenty-three known ones (7-29) from the Piper species. Their structures were established by spectroscopic and spectrometric techniques. Flavonoids were tested for in vitro antiprotozoal activity against Giardia intestinalis trophozoites. In addition, structure-activity relationship (SAR) and in silico ADME studies were performed to understand the pharmacophore and pharmacokinetic properties of these natural compounds. Eight flavonoids from this series exhibited remarkable activity in the micromolar range. Moreover, compound 4 was identified as having a 40-fold greater antiparasitic effect (IC50 61.0 nM) than the clinical reference drug, metronidazole (IC50 2.5 µM). This antiprotozoal potency was coupled with an excellent selectivity index (SI 233) on murine macrophages and in silico drug-likeness. SAR studies revealed that the substitution patterns, type of functional group, and flavonoid skeleton played an essential role in the activity. These findings highlight flavonoid 4 as a promising candidate to develop new drugs for the treatment of Giardia infections.

Viruela del mono (MPOX) en paciente varón heterosexual VIH negativo

Se presenta el caso de un paciente varón de 28 años, heterosexual, con VIH negativo que desarrolló erupción cutánea intensa caracterizada por la presencia de vesículas, pústulas y pápulas umbilicadas confluentes en el pene y región púbica con escasa diseminación en el resto del cuerpo, sin adenopatía ni manifestaciones sistémicas, cuatro días después de haber tenido relaciones sexuales con una prostituta aparentemente sana. El hisopado de las lesiones dérmicas revelaron la presencia de ADN del virus MPOX por PCR en tiempo real. Las pruebas inmunológicas fueron las siguientes: ELISA cuarta generación para VIH y Western Blot negativas, anticuerpos IgM para herpes simplex1=1.2 U/ml, anticuerpos IgM para herpes simplex2=1.9 U/ml, anticuerpos IgM para varicela zóster=0.5 S/CO, FTA-ABS (IgM)=negativo. Se resalta la intensidad de las lesiones cutáneas en el pene y la necesidad de realizar pruebas para descarte de MPOX en prostitutas.

We present the case of a 28-year-old male patient, heterosexual, with negative HIV who developed an intense skin rash characterized by the presence of confluent vesicles, pustules, and umbilicated papules on the penis and pubic region with little spread to the rest of the body, without lymphadenopathy or systemic manifestations, four days after having sexual relations with an apparently healthy prostitute. The swabbing of the dermal lesions revealed the presence of MPOX virus DNA by real-time PCR. The immunological tests were the following: negative fourth-generation ELISA and Western Blot for HIV, IgM antibodies to herpes simplex1=1.2 U/ ml, IgM antibodies to herpes simplex2=1.9 U/ml, IgM antibodies to varicella zoster=0.5 S/CO and negative FTA-ABS (IgM) for syphilis. The intensity of skin lesions on the penis and the need to perform tests to rule out MPOX in prostitutes are highlighted.

(E)-Piplartine Isolated from Piper pseudoarboreum, a Lead Compound against Leishmaniasis.

The current therapies of leishmaniasis, the second most widespread neglected tropical disease, have limited effectiveness and toxic side effects. In this regard, natural products play an important role in overcoming the current need for new leishmanicidal agents. The present study reports a bioassay-guided fractionation of the ethanolic extract of leaves of Piper pseudoarboreum against four species of Leishmania spp. promastigote forms, which afforded six known alkamides (1-6). Their structures were established on the basis of spectroscopic and spectrometric analysis. Compounds 2 and 3 were identified as the most promising ones, displaying higher potency against Leishmania spp. promastigotes (IC50 values ranging from 1.6 to 3.8 µM) and amastigotes of L. amazonensis (IC50 values ranging from 8.2 to 9.1 µM) than the reference drug, miltefosine. The efficacy of (E)-piplartine (3) against L. amazonensis infection in an in vivo model for cutaneous leishmaniasis was evidenced by a significant reduction of the lesion size footpad and spleen parasite burden, similar to those of glucantime used as the reference drug. This study reinforces the therapeutic potential of (E)-piplartine as a promising lead compound against neglected infectious diseases caused by Leishmania parasites.

Actividad antiparasitaria in vitro de plantas de la medicina tradicional Tacana sobre Plasmodium faciparum a través del método fluorométrico-SYBR GreenI / In vitro antiparasitic activity from plants of the Tacana traditional medicine on Plasmodiumfaciparum through thefluorometric method-SYBR GreenI

INTRODUCCIÓN: la presencia de compuestos activos en las plantas las posiciona como una fuente alternativa para el descubrimiento de nuevos fármacos. OBJETIVO: realizar la bioprospección de plantas utilizadas en la medicina tradicional tacana frente a cultivos de Plasmodium falciparum. MÉTODOS: se obtuvieron extractos por maceración en etanol a temperatura ambiente, de 31 órganos colectados de 23 plantas, estos fueron evaluados sobre cultivos asincrónicos de la cepa de Plasmodium falciparum resistente a la Cloroquina (FCR3). A los extractos que mostraron actividad antiplasmódica (CI50<20µg/mL), se evaluó la citotoxicidad (DL50) frente a células HeLa y se calculó el índice de selectividad (IS=DL50/CI50). Los extractos que dieron resultados IS>5, fueron seleccionados como promisorios. RESULTADOS: se obtuvieron 3 plantas muy activas (CI50<10µg/mL); 2 moderadamente activas (10µg/mL20µg/mL). De las 9 plantas que presentaron actividad, solo 2 plantas presentaron IS>5. CONCLUSIONES: incorporar los conocimientos del uso tradicional para realizar las evaluaciones biológicas es de mucha ayuda en la selección de plantas con efectos antiplasmódicos.

INTRODUCTION: the presence of active compounds in plants, converts them as an alternative to find new drugs. OBJECTIVE: carry out the bioprospecting of plants used in Tacana traditional medicine against Plasmodium falciparum cultures. METHODS: from the 31 collected organs of 23 plants, raw extracts were obtained by ethanolic maceration at room temperature and these were evaluated on asynchronic cultures of the strain Plasmodium falciparum resistant to Chloroquine (FCR3). The active extracts (IC50<20µg/mL), were evaluated for cytotoxicity (LD50) against HeLa cells and the Selectivity Index (IS=DL50/IC50) was calculated. The extracts that sowed IS>5were selected as promising. RESULTS: a total of 3 species were very active (IC50<10µg/mL); 2 were moderately active (10µg/mL20µg/mL). From the 9 active plants only 2 presented IS>5. CONCLUSIONS: incorporating the traditional knowledge to carry out biological evaluations is very helpful in the selection of plants with antiplasmodial effects.

Synthesis and Antiplasmodial Activity of 1,2,3-Triazole-Naphthoquinone Conjugates.

A series of 34 1,2,3-triazole-naphthoquinone conjugates were synthesized via copper-catalyzed cycloaddition (CuAAC). They were evaluated for their in vitro antimalarial activity against chloroquine-sensitive strains of Plasmodium falciparum and against three different tumor cell lines (SKBr-3, MCF-7, HEL). The most active antimalarial compounds showed a low antiproliferative activity. Simplified analogues were also obtained and some structure-activity relationships were outlined. The best activity was obtained by compounds 3s and 3j, having IC50 of 0.8 and 1.2 µM, respectively. Molecular dockings were also carried on Plasmodium falciparum enzyme dihydroorotate dehydrogenase (PfDHODH) in order to rationalize the results.

Aplicación del método bioquímico-colorimétrico para identificar agentes trypanocidas / Application of the biochemical-colorimetric method to identify trypanocidal agents

La tripanosomiasis americana es una enfermedad infecciosa desatendida, causada por el parásito protozoo Trypanosoma cruzi, que no cuenta con tratamiento en la fase crónica de esta enfermedad mortal, uno de los desafíos es encontrar terapias efectivas para esta compleja enfermedad, dado que no presenta síntomas asociables a la parasitosis por lo que es desconocida entre los médicos tradicionales. Nuestra Facultad está evaluando la medicina tradicional tacana como fuente de agentes antiparasitarios potenciales. El objetivo de este trabajo fue identificar productos naturales trypanocidas utilizando el método colorimétrico XTT-PMS. Para ello, se realizaron curvas de crecimiento de epimastigotes de T. cruzi y determinamos el tiempo óptimo de realización de los ensayos. Se seleccionó la población inicial de trabajo (3x106 parásitos/mL), las condiciones de incubación (medio LIT, 27ºC, 72 horas) y revelado (XTT-PMS, 4 horas). Con el protocolo optimizado, se realizaron evaluaciones de actividad de drogas control, controles naturales y 20 extractos crudos de plantas medicinales de la amazonía. La actividad se basó en cálculos de concentración inhibitoria media y se consideraron activos las sustancias con CI50<50µg/mL. De los 20 extractos evaluados, el 40% fueron activos. Las plantas más interesantes fueron Sipu sipu (CI50=8.9±1.7µg/mL), Ejije bid'u (CI50=9.1±1.5µg/mL) e Id'ene eidhue (CI50=10.8±1.1µg/mL) con valores de CI50 cercanos a los controles, confirmando la utilidad y potencial del protocolo desarrollado

American trypanosomiasis is listed among the unattended infectious disease, is caused by the protozoan parasite Trypanosoma cruzi, and has no treatment in the chronic phase of this deadly disease. One of the challenges is finding effective therapies for this complex disease, given that it does not present any associated symptoms to the parasitism and is unknown among traditional doctors. Our Faculty is evaluating tacana traditional medicine as a source of potential antiparasitic agents. The objective of this work was to identify trypanocidal natural products using the XTTPMS colorimetric method. For this, growth curves of T. cruzi epimastigotes were made to determine the optimal time to carry out the tests. The initial work population (3x106 parasites/mL), the incubation conditions (medium LIT, 27ºC, 72 hours) and revealed process (XTT-PMS, 4 hours) were selected. With the optimized protocol, activity evaluations of control drugs, natural controls and 20 crude extracts of medicinal plants of the Amazon were carried out. The activity was based on calculations of mean inhibitory concentration and substances with IC50 <50µg/mL were considered active. Of the 20 extracts evaluated, 40% were active. The most interesting plants were Sipu sipu (IC50=8.9±1.7µg/mL), Ejije bid'u (IC50=9.1±1.5µg/mL) and Id'ene eidhue (IC50=10.8±1.1µg/mL) with values of IC50 close to the controls, confirming the usefulness and potential of the developed protocol.

Multilayer Bixin Microcapsules: The Impact of Native Carbohydrates on the Microencapsulation Efficiency and Dispersion Stability.

Bixin is a hydrophobic carotenoid present in the integument of the seeds of Bixa orellana. Microencapsulation was applied to obtain water dispersible formulations and protect the colorant against degradation. Microencapsulated systems were obtained by spray-drying a mild alkaline bixin dispersion with different encapsulating materials. The encapsulation trials were performed with and without native carbohydrates of the integument in addition to the main encapsulant. It was possible to dry dispersions with up to 10% bixin counted on total solids. All the studied systems were characterized by colorimetry, UV-vis spectroscopy, Scanning Electron Microscopy, light microscopy, turbidometric sedimentation analyses and laser light diffraction analyses. All the systems showed aqueous dispersibility but displayed differences in their transparency, UV-vis spectra and physical stability at pH 3. The results show that the native carbohydrates enhance the encapsulation efficiency of other encapsulating materials. The chemical composition of this native carbohydrate fraction shows the presence of polysaccharides containing arabinose, galactose and glucose as monomers. Starch was identified enzymatically. The native carbohydrates allowed the encapsulation of bixin in its native microcrystalline form, resulting in a multilayer structure after spray-drying. In addition, the colorant particles displayed dispersibility under acidic aqueous conditions suggesting that they are stabilized by the native carbohydrates after the microcapsules are dissolved.

An unprecedented chlorine-containing piperamide from Piper pseudoarboreum as potential leishmanicidal agent.

A phytochemical investigation of the ethanolic extract of leaves from Piper pseudoarboreum led to the isolation of 3-chlorosintenpyridone 1, an unprecedented chlorinated piperamide, together with the known compounds 2-12. Their structures were established based on 1D and 2D (COSY, ROESY, HMQC, and HMBC) NMR spectroscopy, in addition to high resolution mass spectrometry. The proposed biosynthetic pathway of compound 1 is discussed. Compounds 1-12 were tested in vitro for their leishmanicidal potential against promastigote stages of Leishmania amazonensis, L braziliensis, L. guyanensis and L. infantum. Two compounds from this series, the alkamide 1 (IC50 3.4-5.2 µM) and the fatty acid 9 (IC50 18.7-29.6 µM) displayed higher or similar potency to Miltefosine, used as the reference drug.

Desparasitación en niños de escuelas rurales 2016-2017: diagnóstico y tratamiento de enteroparásitos intestinales en la escuela de Sapecho A ­ Sud Yungas, La Paz / Deworming in children of rural schools 2016-2017: diagnosis and treatment of intestinal enterocoparasites in Sapecho A School - Sud Yungas, La Paz

Los parásitos intestinales son un grave problema de salud pública donde la alta prevalencia está asociado a la falta de educación sanitaria, hábitos higiénicos e infraestructura inadecuada. El presente trabajo es un estudio descriptivo de corte transversal, donde el universo de trabajo son todos los niños de la Escuela Sapecho A (Gestión 2016-2017), trabajo que involucro a estudiantes de pregrado y de post grado de la Facultad de Ciencia Farmacéuticas y Bioquímicas, donde a través de estudios coproparasitológicos (técnica de Ritchie) se pudo observar que la mayoría de la población, entre 78,24 y 88,4%, se encontraba infectada por uno o más parásitos (Helmintos­Protozoos). Luego de realizar una desparasitación masiva con albendazol (400mg/Dos dosis) se llegó a una reducción respecto a los helmintos de 53,5 y 65,2% respectivamente en cada gestión, sin embargo, este no fue efectivo contra los protozoos. Para alcanzar un éxito en el tratamiento se debe tratar al grupo familiar y dar énfasis al componente educativo de higiene y limpieza.

Intestinal parasites are a serious public health problem where the high prevalence is associated with a lack of education, inadequate hygienic habits and sanitary infrastructure. The present work is a cross-sectional descriptive study, where the universe of work are the children of Sapecho A School (Management 2016-2017), work that involved undergraduate and post-graduate students of the Faculty of Pharmaceutical Science and Biochemistry where through coproparasitological studies (Ritchie's technique) it was observed that the majority of the population, between 78.24 and 88.4%, was infected by one or more parasites (Helminths-Protozoa). After performing a massive deworming treatment with albendazole (400mg/Two doses) a reduction was reached with respect to the helminths of 53.5 and 65.2%, respectively in each year, however this was not effective against the protozoa. To achieve a successful treatment, the family group must be treated and the educational component of hygiene and cleanliness should be emphasized.

Leishmanicidal and cytotoxic activity from plants used in Tacana traditional medicine (Bolivia).

ETNOPHARMACOLOGICAL RELEVANCE: Thirty-eight Tacana medicinal plant species used to treat skin problems, including leishmania ulcers, skin infections, inflammation and wound healing, were collected in the community of Buena Vista, Bolivia, with the Tacana people. Twenty two species are documented for the first time as medicinal plants for this ethnic group living in the northern area of the Department of La Paz. AIM OF THE STUDY: To evaluate the leishmanicidal effect (IC50) and cytotoxicity (LD50) of the selected plants. To carry out bioguided studies on the active extracts. To assess the potential of Bolivian plant biodiversity associated with traditional knowledge in the discovery of alternative sources to fight leishmaniasis. MATERIALS AND METHODS: Seventy three ethanol extracts were prepared from 38 species by maceration and were evaluated in vitro against promastigotes of Leishmania amazonensis and L. braziliensis. Active extracts (IC50 ≤ 50 µg/mL) were fractionated by chromatography on Silica gel column and the fractions were assessed against the two Leishmania strains. The most active fractions and the crude extracts were evaluated against reference strains of L. amazonensis, L. braziliensis, L. aethiopica, two native strains (L. Lainsoni and L. braziliensis) and for cytotoxicity against HeLa cells. The chromatographic profile of the active fractions was obtained by reverse phase chromatography using HPLC. RESULTS: From the 73 extracts, 39 extracts (53.4%) were inactive and 34 showed activity. Thirteen species were sselected for bioguided studies. The crude extracts and their 36 fractions were evaluated against two Leishmania strains. The most active fraction were tested in a panel of five leishmania strains and for cytotoxicity. The Selective Index (SI = LD50/IC50) was calculated, and were generally low. Retention time and UV spectra were recorded for the active fractions by HPLC-DAD using a reverse phase column. Profiles were very different from each other, showing the presence of different compounds. CONCLUSION: Bolivian traditional knowledge from the Tacanba was useful to identify plants with effect on Leishmania promastigotes. Chromatographic bioguided studies showed stronger leishmanicidal and cytotoxic activity for the medium polar fraction. HPLC analysis showed different chromatographic profiles of the active fractions.

Leishmaniasis in the major endemic region of Plurinational State of Bolivia: Species identification, phylogeography and drug susceptibility implications.

The Plurinational State of Bolivia is one of the Latin American countries with the highest prevalence of leishmaniasis, highlighting the lowlands of the Department of La Paz where about 50% of the total cases were reported. The control of the disease can be seriously compromised by the intrinsic variability of the circulating species that may limit the efficacy of treatment while favoring the emergence of resistance. Fifty-five isolates of Leishmania from cutaneous and mucocutaneous lesions from patients living in different provinces of the Department of La Paz were tested. Molecular characterization of isolates was carried out by 3 classical markers: the rRNA internal transcribed spacer 1 (ITS-1), the heat shock protein 70 (HSP70) and the mitochondrial cytochrome b (Cyt-b). These markers were amplified by PCR and their products digested by the restriction endonuclease enzymes AseI and HaeIII followed by subsequent sequencing of Cyt-b gene and ITS-1 region for subsequent phylogenetic analysis. The combined use of these 3 markers allowed us to assign 36 isolates (65.5%) to the complex Leishmania (Viannia) braziliensis, 4 isolates (7, 27%) to L. (Viannia) lainsoni. and the remaining 15 isolates (23.7%) to a local variant of L. (Leishmania) mexicana. Concerning in vitro drug susceptibility the amastigotes from all isolates where highly sensitive to Fungizone® (mean IC50 between 0.23 and 0.5µg/mL) whereas against Glucantime® the sensitivity was moderate (mean IC50 ranging from 50.84µg/mL for L. (V.) braziliensis to 18.23µg/mL for L. (L.) mexicana. L. (V.) lainsoni was not sensitive to Glucantime®. The susceptibility to miltefosine was highly variable among species isolates, being L. (L.) mexicana the most sensitive, followed by L. (V.) braziliensis and L. (V.) lainsoni (mean IC50 of 8.24µg/mL, 17.85µg/mL and 23.28µg/mL, respectively).

Estudios de susceptibilidad de cepas de Leishmania aethiopica frente a alcaloides de Galipea longiflora (Evanta) / Susceptibility studies on Leishmania aethiopica strains against total alkaloids from Galipea longiflora (Evanta)

El Instituto de Investigaciones Fármaco Bioquímicas (IIFB), de la Facultad de Ciencias Farmacéuticas y Bioquímicas, de la UMSA, desarrolla trabajos sobre la actividad leishmanicida, de los alcaloides totales (CAT) obtenidos de la corteza de la especie medicinal amazónica conocida como Evanta (Galipea longiflora) por los Pueblos Tacana, Tsimane y Mosetene. Como parte de las actividades del Proyecto UMSA-ASDI Biomoleculas de interés medicinal e industrial (antiparasitarios) hemos podido contar con la estadía, en el IIFB, de un investigador del Armauer Hansen Research Institute (AHRI) de Etiopia, lo que nos ha permitido desarrollar evaluaciones de CAT, Miltefocine y Amfotericina B, frente a cepas de Leishmania aethiopica, agente causante de las diversa formas de Leishmaniais cutánea en Etiopía. Un total de seis cepas, de L. aethiopica, fueron adaptadas a condiciones in vitro y mostraron un comportamiento homogéneo frente a CAT, cinco de estas cepas mostraron un valor promedio de IC50 = 8,68 ±1,56 mg/mL, valor algo inferior a los calculados para nuestras cepas de referencia, L. amazonensis y L. braziliensis con IC50 = 11,73 ± 4,32 mg/mL y IC50 = 12,28 ±- 2,95 mg/mL, respectivamente. Excepto por una cepa de L. aethiopica que mostro valores consistentemente más elevados que el resto con IC50= 14,37 ± 3,58 mg/mL. Como consecuencia de esta interacción científica, la Universidad Mayor de San Andrés (UMSA) ha firmado un Memorandum de Entendimiento para el desarrollo de investigaciones conjuntas, con el Armauer Hansen Research Institute (AHRI), dependiente del Ministerio de Salud de Etiopia y explorar la posibilidad de que nuestra experiencia de validación clínica con Evanta en el tratamiento de leishmaiasis cutánea, en Bolivia, podría ser replicada en Etiopía, donde se reportan entre 20,000 a 30,000 nuevos casos de Leismaniasis por año.

The Instituto de Investigaciones Fármaco Bioquímicas (IIFB), at the Faculty of Pharmaceutical and Biochemical Sciences, from UMSA, carry out work related to the leishmanicidal activity of the total alkaloids (CAT) obtained from the bark of the Amazonian medicinal species known as Evanta (Galipea longiflora) by the Tacana, Tsimane y Mosetene people. As part of the activities develop by the UMSA-ASDI Project Biomolecules of medicinal and industrial Interest (antiparasitic) we had a visit, in our laboratories at IIFB, of a researcher from The Armauer Hansen Research Institute (AHRI) from Ethiopia, during his stay we were able to carry out evaluations of CAT, Miltefocine and Anphotericin B, against strains of L. aethiopica, causative agent of the different manifestations of cutaneous leishmaniasis in Ethiopia. A total of six strains of L. aethiopica, were adapted to in vitro a conditions, at IIFB; and did show homogenous behavior against CAT. Five of the strains, showed an average calculated value for IC50 = 8.68 ±1.56 mg/mL, a value somewhat lower to the calculated for the reference strains L. amazonensis and L. braziliensis with IC50 = 11.73 ± 4.32 mg/mL and IC50 = 12.28 +/- 2.95 mg/mL, respectively. Except for one strain that showed values somewhat higher, to the other strains, consistently through our studies, with IC50 = 14.37 ± 3.58 mg/mL. As a consequence of our scientific interaction, the Universidad Mayor de San Andrés (UMSA) has signed a Memorandum of Understanding for the development of joint research with the Armauer Hansen Research Institute (AHRI) that belongs to the Ministry of Health in Ethiopia, and explore the possibilities to replicate the Bolivian clinical validation experience of Evanta in the treatment of cutaneous leishmaniasis, in Ethiopia where the annual incidence is estimated to be between 20, 000 to 30, 0000.

Flavonoids from Piper delineatum modulate quorum-sensing-regulated phenotypes in Vibrio harveyi.

Quorum sensing (QS), or bacterial cell-to-cell communication, is a key process for bacterial colonization of substrata through biofilm formation, infections, and production of virulence factors. In an ongoing investigation of bioactive secondary metabolites from Piper species, four new flavonoids (1-4), along with five known ones (5-9) were isolated from the leaves of Piper delineatum. Their stereostructures were established by spectroscopic and spectrometric methods, including 1D and 2D NMR experiments, and comparison with data reported in the literature. The compounds were screened for their ability to interfere with QS signaling in the bacterial model Vibrio harveyi. Four compounds from this series (2, 3, 6, and 7) exhibited remarkable activity in the micromolar range, being compounds 3 and 7 particularly attractive since they did not affect bacterial growth. The results suggest that these flavonoids disrupt QS-mediated bioluminescence by interaction with elements downstream LuxO in the QS circuit of V. harveyi, and also, they exhibited a strong dose-dependent inhibition of biofilm formation. The present findings shed light on the QS inhibition mechanisms of flavonoids, underlining their potential applications.

Evaluation of substituted phenalenone analogues as antiplasmodial agents.

A set of derivatives encompassing structural modifications on the privileged phenalenone scaffold were assessed for their antiplasmodial activities against a strain of chloroquine sensitive Plasmodium falciparum F32. Two compounds exhibited considerable effects against the malaria parasite (IC50 ≤ 1 µg/mL), one of which maintained the same level of activity in a chloroquine-resistant strain. This is the first record of antiplasmodial activity on this type of scaffold, providing a new structural motif as a new lead for antimalarial activity.

Preparation and antimalarial activity of semisynthetic lycorenine derivatives.

A set of twenty one lycorenine derivatives has been prepared from the alkaloid hippeastrine (1). The modifications performed on hippeastrine included some functional group transformations, structural simplification and preparation of dimers. All alkaloids were tested as potential antimalarial agents, being the hippeastrine dimers the most active compounds.

Synthesis and antimalarial activity of new haemanthamine-type derivatives.

Thirty one derivatives were prepared from the natural alkaloids haemanthamine (1), haemanthidine (2) and 11-hydroxyvittatine (3). They were evaluated for their in vitro antimalarial activity against chloroquine-sensitive strains of Plasmodium falciparum and some structure-activity relationships were outlined. For haemanthamine derivatives having a methoxy group at C-3, the presence of a free hydroxyl group at C-11 is important for the activity. The double bond at C-1-C-2 plays also an important role to achieve good inhibitory activity. Compound 35 with two nicotinate groups at C-3 and at C-11 was the most active compound with a IC(50) = 0.8 ± 0.06 µM.

Synthesis and antiplasmodial activity of lycorine derivatives.

Twenty seven lycorine derivatives were prepared and evaluated for their in vitro antimalarial activity against chloroquine-sensitive strains of Plasmodium falciparum. The best antiplasmodial activities were achieved with lycorine derivatives that present free hydroxyl groups at C-1 and C-2 or esterified as acetates or isobutyrates. The double bond C-2-C-3 is also important for the activity. Concerning to the antiplasmodial activity of the secolycorines, the higher values were obtained with the replacement of the methylenedioxy moiety by hydroxyl or acetate groups and with methyl substituent attached to the nitrogen atom.

Antiparasitic activity of prenylated benzoic acid derivatives from Piper species.

Fractionation of dichloromethane extracts from the leaves of Piper heterophyllum and P. aduncum afforded three prenylated hydroxybenzoic acids, 3-[(2E,6E,10E)-11-carboxy-3,7,15-trimethyl-2,6,10,14-hexadecatetraenyl)-4,5-dihydroxybenzoic acid, 3-[(2E,6E,10E)-11-carboxy-13-hydroxy-3,7,15-trimethyl-2,6,10,14-hexadecatetraenyl]-4,5-dihydroxybenzoic acid and 3-[(2E,6E,10E)-11-carboxy-14-hydroxy-3,7,15-trimethyl-2,6,10,15-hexadecatetraenyl]-4,5-dihydroxybenzoic acid, along with the known compounds, 4,5-dihydroxy-3-(E,E,E-11-formyl-3,7,15-trimethyl-hexadeca-2,6,10,14-tetraenyl)benzoic acid (arieianal), 3,4-dihydroxy-5-(E,E,E-3,7,11,15-tetramethyl-hexadeca-2,6,10,14-tetraenyl)benzoic acid, 4-hydroxy-3-(E,E,E-3,7,11,15-tetramethyl-hexadeca-2,6,10,14-tetraenyl)benzoic acid, 3-(3,7-dimethyl-2,6-octadienyl)-4-methoxy-benzoic acid, 4-hydroxy-3-(3,7-dimethyl-2,6-octadienyl)benzoic acid and 4-hydroxy-3-(3-methyl-1-oxo-2-butenyl)-5-(3-methyl-2-butenyl)benzoic acid. Their structures were elucidated on the basis of spectroscopic data, including homo- and heteronuclear correlation NMR experiments (COSY, HSQC and HMBC) and comparison with data reported in the literature. Riguera ester reactions and optical rotation measurements established the compounds as racemates. The antiparasitic activity of the compounds were tested against three strains of Leishmania spp., Trypanosoma cruzi and Plasmodium falciparum. The results showed that 3-(3,7-dimethyl-2,6-octadienyl)-4-methoxy-benzoic acid exhibited potent and selective activity against L. braziliensis (IC(50) 6.5 microg/ml), higher that pentamidine used as control. Moreover, 3-[(2E,6E,10E)-11-carboxy-3,7,15-trimethyl- 2,6,10,14-hexadecatetraenyl)-4,5-dihydroxybenzoic acid and 4-hydroxy-3-(3-methyl-1-oxo-2-butenyl)-5-(3-methyl-2-butenyl)benzoic acid showed moderate antiplasmodial (IC(50) 3.2 microg/ml) and trypanocidal (16.5 microg/ml) activities, respectively.

Bioactive montanine derivatives from halide-induced rearrangements of haemanthamine-type alkaloids. Absolute configuration by VCD.

An unexpected rearrangement of haemanthamine-type alkaloids in the presence of halogenating agents has been found. Rearranged compounds present the 5,11-methanomorphantridine framework characteristic of montanine-type alkaloids. These compounds are difficult to obtain because of their scarcity in natural sources and because the synthetic approaches developed so far require numerous steps. Vibrational circular dichroism (VCD) spectroscopy was used to determine the absolute configuration of one of the rearranged compounds. Several rearranged alkaloids showed antimalarial activity.

Benzoic acid derivatives from Piper species and their antiparasitic activity.

Piper glabratum and P. acutifolium were analyzed for their content of main secondary constituents, affording nine new benzoic acid derivatives (1, 2, 4, 5, 7, and 10-13), in addition to four known compounds (3, 6, 8, and 9). Their structures were elucidated on the basis of spectroscopic data. Riguera ester reactions and optical rotation measurements established the new compounds as racemates. In the search for antiparasitic agents, the compounds were evaluated in vitro against the promastigote forms of Leishmania spp., Trypanosoma cruzi, and Plasmodium falciparum. Among the evaluated compounds, methyl 3,4-dihydroxy-5-(3'-methyl-2'-butenyl)benzoate (7) exhibited leishmanicidal effect (IC50 13.8-18.5 microg/mL) against the three Leishmania strains used, and methyl 3,4-dihydroxy-5-(2-hydroxy-3-methylbutenyl)benzoate (1), methyl 4-hydroxy-3-(2-hydroxy-3-methyl-3-butenyl)benzoate (3), and methyl 3,4-dihydroxy-5-(3-methyl-2-butenyl) benzoate (7) showed significant trypanocidal activity, with IC50 values of 16.4, 15.6, and 18.5 microg/mL, respectively.