RESUMO
The antibiotic tetracycline demeclocycline (DMC) was recently reported to rescue α-synuclein (α-Syn) fibril-induced pathology. However, the antimicrobial activity of DMC precludes its potential use in long-term neuroprotective treatments. Here, we synthesized a doubly reduced DMC (DDMC) derivative with residual antibiotic activity and improved neuroprotective effects. The molecule was obtained by removal the dimethylamino substituent at position 4 and the reduction of the hydroxyl group at position 12a on ring A of DMC. The modifications strongly diminished its antibiotic activity against Gram-positive and Gram-negative bacteria. Moreover, this compound preserved the low toxicity of DMC in dopaminergic cell lines while improving its ability to interfere with α-Syn amyloid-like aggregation, showing the highest effectiveness of all tetracyclines tested. Likewise, DDMC demonstrated the ability to reduce seeding induced by the exogenous addition of α-Syn preformed fibrils (α-SynPFF) in biophysical assays and in a SH-SY5Y-α-Syn-tRFP cell model. In addition, DDMC rendered α-SynPFF less inflammogenic. Our results suggest that DDMC may be a promising drug candidate for hit-to-lead development and preclinical studies in Parkinson's disease and other synucleinopathies.
Assuntos
Neuroblastoma , Fármacos Neuroprotetores , Sinucleinopatias , Antibacterianos/farmacologia , Demeclociclina , Bactérias Gram-Negativas , Bactérias Gram-Positivas , Humanos , Chumbo , Fármacos Neuroprotetores/farmacologiaRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: In the Peruvian Amazon as in the tropical countries of South America, the use of medicinal Piper species (cordoncillos) is common practice, particularly against symptoms of infection by protozoal parasites. However, there is few documented information about the practical aspects of their use and few scientific validation. The starting point of this work was a set of interviews of people living in six rural communities from the Peruvian Amazon (Alto Amazonas Province) about their uses of plants from Piper genus: one community of Amerindian native people (Shawi community) and five communities of mestizos. Infections caused by parasitic protozoa take a huge toll on public health in the Amazonian communities, who partly fight it using traditional remedies. Validation of these traditional practices contributes to public health care efficiency and may help to identify new antiprotozoal compounds. AIMS OF STUDY: To record and validate the use of medicinal Piper species by rural people of Alto Amazonas Province (Peru) and annotate active compounds using a correlation study and a data mining approach. MATERIALS AND METHODS: Rural communities were interviewed about traditional medication against parasite infections with medicinal Piper species. Ethnopharmacological surveys were undertaken in five mestizo villages, namely: Nueva Arica, Shucushuyacu, Parinari, Lagunas and Esperanza, and one Shawi community (Balsapuerto village). All communities belong to the Alto Amazonas Province (Loreto region, Peru). Seventeen Piper species were collected according to their traditional use for the treatment of parasitic diseases, 35 extracts (leaves or leaves and stems) were tested in vitro on P. falciparum (3D7 chloroquine-sensitive strain and W2 chloroquine-resistant strain), Leishmania donovani LV9 strain and Trypanosoma brucei gambiense. Assessments were performed on HUVEC cells and RAW 264.7 macrophages. The annotation of active compounds was realized by metabolomic analysis and molecular networking approach. RESULTS: Nine extracts were active (IC50 ≤ 10 µg/mL) on 3D7 P. falciparum and only one on W2 P. falciparum, six on L. donovani (axenic and intramacrophagic amastigotes) and seven on Trypanosoma brucei gambiense. Only one extract was active on all three parasites (P. lineatum). After metabolomic analyses and annotation of compounds active on Leishmania, P. strigosum and P. pseudoarboreum were considered as potential sources of leishmanicidal compounds. CONCLUSIONS: This ethnopharmacological study and the associated in vitro bioassays corroborated the relevance of use of Piper species in the Amazonian traditional medicine, especially in Peru. A series of Piper species with few previously available phytochemical data have good antiprotozoal activity and could be a starting point for subsequent promising work. Metabolomic approach appears to be a smart, quick but still limited methodology to identify compounds with high probability of biological activity.
Assuntos
Antiprotozoários/metabolismo , Etnofarmacologia/métodos , Medicina Tradicional/métodos , Metabolômica/métodos , Piper/metabolismo , Extratos Vegetais/metabolismo , Animais , Antimaláricos/isolamento & purificação , Antimaláricos/metabolismo , Antimaláricos/uso terapêutico , Antiprotozoários/isolamento & purificação , Antiprotozoários/uso terapêutico , Feminino , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Leishmania donovani/efeitos dos fármacos , Leishmania donovani/metabolismo , Mesocricetus , Camundongos , Peru/etnologia , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/uso terapêutico , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/metabolismo , Células RAW 264.7 , Inquéritos e QuestionáriosRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: In the Peruvian Amazon, the use of medicinal plants is a common practice. However, there is few documented information about the practical aspects of their use and few scientific validation. The starting point for this work was a set of interviews of people living in rural communities from the Peruvian Amazon about their uses of plants. Protozoan diseases are a public health issue in the Amazonian communities, who partly cope with it by using traditional remedies. Validation of these traditional practices contributes to public health care efficiency and may help identify new antiprotozoal compounds. AIMS OF STUDY: to inventory and validate the use of medicinal plants by rural people of Loreto region. MATERIALS AND METHODS: Rural mestizos were interviewed about traditional medication of parasite infections with medicinal plants. Ethnopharmacological surveys were undertaken in two villages along Iquitos-Nauta road (Loreto region, Peru), namely 13 de Febrero and El Dorado communities. Forty-six plants were collected according to their traditional use for the treatment of parasitic diseases, 50 ethanolic extracts (different parts for some of the plants) were tested in vitro on Plasmodium falciparum (3D7 sensitive strain and W2 chloroquine resistant strain), Leishmania donovani LV9 strain and Trypanosoma brucei gambiense. Cytotoxic assessment (HUVEC cells) of the active extracts was performed. Two of the most active plants were submitted to preliminary bioguided fractionation to ascertain and explore their activities. RESULTS: From the initial plants list, 10 were found to be active on P. falciparum, 15 on L. donovani and 2 on the three parasites. The ethanolic extract from Costus curvibracteatus (Costaceae) leaves and Grias neuberthii (Lecythidaceae) bark showed strong in vitro activity on P. falciparum (sensitive and resistant strain) and L. donovani and moderate activity on T. brucei gambiense. CONCLUSIONS: The Amazonian forest communities in Peru represents a source of knowledge on the use of medicinal plants. In this work, several extracts with antiprotozoal activity were identified. This work contributes to validate some traditional uses and opens subsequent investigations on active compounds isolation and identification.
Assuntos
Antiprotozoários/farmacologia , Medicina Tradicional/métodos , Extratos Vegetais/farmacologia , Plantas Medicinais/química , Animais , Antiprotozoários/isolamento & purificação , Cricetinae , Etnofarmacologia , Feminino , Células Endoteliais da Veia Umbilical Humana , Humanos , Leishmania donovani/efeitos dos fármacos , Testes de Sensibilidade Parasitária , Peru , Extratos Vegetais/isolamento & purificação , Plasmodium falciparum/efeitos dos fármacos , Infecções por Protozoários/tratamento farmacológico , Infecções por Protozoários/parasitologia , População Rural , Inquéritos e Questionários , Trypanosoma brucei gambiense/efeitos dos fármacosRESUMO
Zanthoxylum chiloperone var. angustifolium root bark was studied with the aim of finding novel molecules able to overcome cancer stem cell chemoresistance. Purification of a methanol-soluble extract resulted in the isolation of a known pyranocoumarin, trans-avicennol (1). Compound 1 demonstrated antiproliferative activity on glioma-initiating cells, whereas it was inactive on human neural stem cells. trans-Avicennol (1) activated the MAPK/ERK pathway and was also evaluated for its ability to inhibit the enzyme indoleamine-2,3-dioxygenase.
Assuntos
Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Cumarínicos/isolamento & purificação , Cumarínicos/farmacologia , Células-Tronco Neurais/efeitos dos fármacos , Pironas/isolamento & purificação , Pironas/farmacologia , Zanthoxylum/química , Animais , Antineoplásicos Fitogênicos/química , Cumarínicos/química , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Camundongos , Quinases de Proteína Quinase Ativadas por Mitógeno/efeitos dos fármacos , Estrutura Molecular , Paraguai , Casca de Planta/química , Pironas/química , EstereoisomerismoRESUMO
Zanthoxylum chiloperone var. angustifolium Engl., Rutaceae, is used in traditional medicine to treat fungal and protozoal infections in the central area of South America. Considering the increasing resistance of Plasmodium falciparum in malarial ridden areas, we explored the anti-plasmodial effects of three compounds isolated from Z. chiloperone. The pyranocoumarin transavicennol and the canthinone alkaloids, canthin-6-one and 5-methoxycanthin-6-one, were found to have IC50 on chloroquine/mefloquine resistant and sensitive strains of P. falciparum of 0.5-2.7, 2.0-5.3 and 5.1-10.4 Êg/mL, respectively. Moreover, the formation of heme adducts by these compounds is described by a novel alternative method based on MS-CID methods. The alkylamide sanshool was also identified, for first time in this plant, in the dichloromethanic and ethanolic extracts and the extracts were found to be notably non-toxic and displayed good anti-plasmodial effects.
RESUMO
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.
Assuntos
Antiprotozoários/isolamento & purificação , Antiprotozoários/farmacologia , Cumarínicos/isolamento & purificação , Cumarínicos/farmacologia , Leishmania/efeitos dos fármacos , Plantas Medicinais/química , Rutaceae/química , Antiprotozoários/química , Colômbia , Cumarínicos/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Células Precursoras de Monócitos e Macrófagos/efeitos dos fármacos , Ressonância Magnética Nuclear Biomolecular , Folhas de Planta/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Actualmente la quimioterapia de la leishmaniasis es promisoria, sin embargo aun no se dispone de un medicamento adecuado. Varias quinolinas sustituidas han presentado actividad in vitro contra agentes causales de leishmaniasis cutánea, leishmaniasis visceral, tripanosomiasis africana y enfermedad de Chagas. En este trabajo se sintetizan seis 2-arilquinolinas derivadas de la galipeina mediante condensación de Perkin a partir de quinaldina y aldehídos aromáticos. La actividad leishmanicida se evalúa en amastigotes axénicos y la actividad citotóxica en células U-937. Todos los compuestos muestran ser activos contra leishmania panamensis pero también contra células mamíferas. Los compuestos estirilquinolinas 2-[(E)-2-(2,5-dimetoxifenil)etenil]quinolina (1), 2-[(E)-2-(2,3-dimetoxifenil)etenil]quinolina (2) y N-{4-[(E)-2-quinolin-2-iletenil]fenil}acetamida (3) son mas activos sobre amastigotes axénicos (CE50 = 3,7; 4,5 y 19,1μg/mL) e intracelulares (CE50 = 1,4; 1,8 y 1,7μg/mL), en comparación con los derivados hidrogenados 2-[2-(2,5-dimetoxifenil)etil]quinolina (1a), 2-[2-(2,3-dimetoxifenil)etil]quinolina (2a) y N-[4-(2-quinolin-2-iletil)fenil]acetamida (3a) (CE50= 31,1; 23,6 y 59,3μg/mL). Todos los compuestos muestran también actividad contra células U-937 con CE50 de 3,7; 6,2 y 4,5μg/mL para las estirilquinolinas 1, 2 y 3, respectivamente y CE50 de 16,0; 12,9 y 20,2μg/mL para los derivados hidrogenados 1a, 2a y 3a, respectivamente. Aunque el proceso de hidrogenación produjo una disminución tanto de la actividad leishmanicida como de la actividad citotóxica, la actividad leishmanicida mostrada por los compuestos de tipo 2-estirilquinolinas les confiere un potencial como moléculas candidatas para el desarrollo de compuestos anti-leishmania.
The search of new treatments for leishmaniasis is an active task nowadays, since there is a lack of non-toxic, cheap and non-resistant medication. In the literature several quinolines have shown in vitro activity against agents of cutaneous leishmaniasis, visceral leishmaniasis, African trypanosomiasis and Chagas diseases. Six 2-styrylquinolines derived from galipeine were synthesized by Perkin condensation of quinaldine with aromatic aldehydes. Leishmanicidal activity was estimated for leishmania panamensis at the amastigote form and cytotoxic activity against U-937 cells. All compounds showed activity against both L. panamensis and U-937 cells. (E)-2-(2,5-dimethoxyphenyl)ethenyl)quinoline (1), (E)-2-(2,3-dimethoxyphenyl)ethenyl)quinoline (2) and (E)-N-[4-(2-quinolin-2-yl-ethenyl)phenyl]acetamide (3) were more active against axenic (EC50= 3.7, 4.5 and 19.1μg/mL) and intracellular amastigotes (EC50= 1.4, 1.8 and 1.7μg/ml, respectively), in comparison with hydrogenated derivatives 2-[2-(2,5-dimethoxyphenyl)ethyl]quinoline (1a), 2-[2-(2,3-dimethoxyphenyl)ethyl]quinoline (2a) and N-[4-(2-quinolin-2-ylethyl)phenyl]acetamide (3a) (CE50= 31.1, 23.6 and 59.3μg/mL, respectively). All compounds were also active against the U-937 cells. Styrylquinolines 1, 2 and 3 showed a LC50 of 3.7, 6.2 and 4.5μg/mL, respectively and the hydrogenated derivatives 1a, 2a and 3a showed a LC50 of 16.0. 12.9 and 20.2μg/mL, respectively. Although hydrogenation reduced the leishmanicidal and cytotoxic activities, the activity showed against leishmania parasites suggests this compound series has potential as drug candidates for the treatment of leishmaniasis.
RESUMO
In vitro spontaneous proliferation is the immunological hallmark of peripheral blood mononuclear cells (PBMC) from HTLV-1-infected individuals. Quinoline compounds down regulate in vitro cell proliferation of HTLV-1 transformed cell lines. In the present study we assessed the capacity of quinolines to inhibit spontaneous cell proliferation of PBMC from HTLV-1-infected individuals. Twenty-two quinolines were evaluated. Toxicity was first assessed on PBMC from healthy donors by using both the Trypan blue technique and Tetrazolium Salt (XTT) method and then the antiproliferative effect was measured by a classic lymphoproliferative assay on PBMC from three HTLV-1-infected individuals, in the presence of decreasing concentrations of quinolines (from 100microM to 0.8microM), after 5 days of culture. We found that 14 out of 22 compounds were non-toxic to PBMC from uninfected individuals at 100, 50 and 10microM. Four compounds presented a capacity to inhibit more than 80% of the spontaneous proliferation: 7 at 25microM and 10, 20 and 23 at 100microM. Our results indicate that some quinolines block spontaneous proliferation of PBMC from HTLV-1-infected individuals.
Assuntos
Infecções por HTLV-I/patologia , Monócitos/efeitos dos fármacos , Quinolinas/farmacologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Ensaio de Imunoadsorção Enzimática , Humanos , Indicadores e Reagentes , Sais de Tetrazólio , Azul TripanoRESUMO
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.
Assuntos
Annonaceae/química , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/farmacologia , Edema/induzido quimicamente , Interleucina-1beta/biossíntese , Plantas Medicinais/química , Triterpenos/isolamento & purificação , Triterpenos/farmacologia , Animais , Anti-Inflamatórios/química , Carragenina/farmacologia , Colômbia , Interleucina-1beta/efeitos dos fármacos , Camundongos , Folhas de Planta/química , Triterpenos/químicaRESUMO
We report in this study the in vivo efficacy of nine 2-substituted quinolines on the Leishmania amazonensis cutaneous infection murine model and on the Leishmania infantum and Leishmania donovani visceral infection murine models. In the case of the L. amazonensis model, quinolines were administered orally at 25 mg/kg twice daily for 15 days. Quinolines 1, 2, 3, and 7 reduced by 80 to 90% the parasite burdens in the lesion, whereas N-methylglucamine antimoniate (Glucantime), administered by subcutaneous injections at 100 mg [28 mg Sb(V)] per kg of body weight daily, reduced the parasite burdens by 98%. In visceral leishmaniasis due to L. infantum, mice treated orally at 25 mg/kg daily for 10 days with quinolines 1, 4, 5, and 6 showed a significant reduction of parasite burdens in the liver and spleen. These quinolines were significantly more effective than meglumine antimoniate to reduce the parasite burden in both the liver and spleen. Also, the oral in vivo activity of three quinolines (quinolines 4, 5, and 2-n-propylquinoline) were determined against L. donovani (LV 9) at 12.5 and 25 mg/kg for 10 days. Their activity was compared with that of miltefosine at 7.5 mg/kg. Miltefosine, 2-n-propylquinoline, and quinoline 5 at 12.5 mg/kg significantly reduced the parasite burdens in the liver by 72, 66, and 61%, respectively. From the present study, quinoline 5 is the most promising compound against both cutaneous and visceral leishmaniasis. The double antileishmanial and antiviral activities of these compounds suggest that this series could be a potential treatment for coinfection of Leishmania-human immunodeficiency virus.