New prenylated quinones from Peperomia galioides

Two new prenylated quinones, piperogalone and galopiperone, and a new prenylated dihydroquinone, hydropiperone, were isolated from #Peperomia galioides H.B.K (#Piperaceae). Hydropiperone exhibited potent antiparasitic activity against three species of #Leishmania$. (Résumé d'auteur

In vitro and in vivo leishmanicidal studies of Peperomia galioides (Piperaceae)

Petroleum ether and methylene chloride extracts of #Peperomia galioides and three phenylated diphenols, grifolic acid, grifolin and piperogalin exhibited in vitro antileishmanial activity. During the course of infection of BALB/c mice with #Leishmania amazonensis, the treatments with each of these compounds did not influence the progression of the disease. (Résumé d'auteur

Preclinical Studies in Anti-Trypanosomatidae Drug Development

The trypanosomatid parasites Trypanosoma brucei, Trypanosoma cruzi and Leishmania are the causative agents of human African trypanosomiasis, Chagas Disease and Leishmaniasis, respectively. These infections primarily affect poor, rural communities in the developing world, and are responsible for trapping sufferers and their families in a disease/poverty cycle. The development of new chemotherapies is a priority given that existing drug treatments are problematic. In our search for novel anti-trypanosomatid agents, we assess the growth-inhibitory properties of >450 compounds from in-house and/or “Pathogen Box” (PBox) libraries against L. infantum, L. amazonensis, L.braziliensis, T. cruzi and T. brucei and evaluate the toxicities of the most promising agents towards murine macrophages. Screens using the in-house series identified 17 structures with activity against and selective toward Leishmania: Compounds displayed 50% inhibitory concentrations between 0.09 and 25 μM and had selectivity index values >10. For the PBox library, ~20% of chemicals exhibited anti-parasitic properties including five structures whose activity against L. infantum had not been reported before. These five compounds displayed no toxicity towards murine macrophages over the range tested with three being active in an in vivo murine model of the cutaneous disease, with 100% survival of infected animals. Additionally, the oral combination of three of them in the in vivo Chagas disease murine model demonstrated full control of the parasitemia. Interestingly, phenotyping revealed that the reference strain responds differently to the five PBox-derived chemicals relative to parasites isolated from a dog. Together, our data identified one drug candidate that displays activity against Leishmania and other Trypanosomatidae in vitro and in vivo, while exhibiting low toxicity to cultured mammalian cells and low in vivo acute toxicity

Cryptofolione derivatives from Cryptocarya alba fruits

Schmeda-Hirschmann G.; Astudillo L. Instituto de Química de Recursos Naturales, Universidad de Talca, Casilla 747, Talca, Chile.Cryptofolione (1) and the new cryptofolione derivative 6-(4,6-dimethoxy-8-phenyl-octa-1,7-dienyl)-4-hydroxy-tetrahydro-pyran-2-one (2) were isolated from the fruits of Cryptocarya alba. The structures were elucidated by spectroscopic methods. Cryptofolione showed activity towards Trypanosoma cruzi trypomastigotes, reducing their number by 77% at 250g mL-1. Cryptofolione showed moderate cytotoxicity in both macrophages and T. cruzi amastigotes. It also displayed a mild inhibitory effect on the promastigote form of Leishmania spp. As both cytotoxic and trypanocidal effects are similar, the compound presented little selectivity in our assay models

Bioactive alkyl phenols and embelin from Oxalis erythrorhiza

Rodriguez,J.;Theoduloz,C. Laboratorio de Cultivo Celular, Facultad de Ciencias de la Salud, Universidad de Talca, Casilla 747, Talca, Chile Schmeda-Hirschmann, G. Natural Products Chemistry Laboratory, Institute of Chemistry of Natural Resources, University of Talca, Talca, Chile.The benzoquinone embelin and four alkyl phenols were isolated from an Argentinean collection of Oxalis erythrorhiza. 3-Heptadecyl-5-methoxy-phenol is reported for the first time. The structures were determined by spectroscopic methods. Embelin presented inhibitory effect on methicillin-resistant Staphylococcus aureus, Escherichia coli and the dermatophytic fungi Epidermophyton floccosum, Microsporum canis, Microsporum gypseum, Trichophyton mentagrophytes and Trichophyton rubrum with MICs ranging between 50 and 100 μg/ml. Furthermore, embelin was active against Trypanosoma cruzi trypomastigotes with 100% lysis at 100 μg/ml and cytotoxicity below the trypanocidal concentration. The new alkyl phenol 3-heptadecyl-5-methoxy-phenol was active towards Leishmania amazonensis and Leishmania donovani promastigotes with 100% lysis at 100 μg/ml. The cytotoxicity (IC50) of embelin and the new alkyl phenol on human lung fibroblasts were 739 and 366 μM, respectively. The plant is used to treat heart complains, a symptomatology related to Chagas’ disease which is endemic in the San Juan Province, Argentine

Synthesis and in vitro antiprotozoal activity of thiophene ring-containing quinones

A series of quinones (3a-i, 4-9, 11) and aromatic compounds (2a, 2d, 2g) containing the thiophene ring were tested in vitro against the trypomastigote form of #Trypanosoma cruzi and the promastigote forms of #Leishmania. The quiones 3a-i, 4, 5a, b, 6 and 9 having the thiophene ring fused to a quinone nucleus were the most active members of the series. The electron affinities of the benzo(b)thiophene-4,7-quinones 3, evaluated by their LUMO energies and halfwave potentials, are reported. (Résumé d'auteur

Trypanocidal bisbenzylisoquinoline alkaloids are inhibitors of trypanothione reductase

Eleven bisbenzylisoquinoline (BBIQ) alkaloids were studied for in vitro trypanocidal activity against trypomastigote forms of the Y strain of #Trypanosoma cruzi$. The inhibitory activity of these compounds against trypanothione reductase (TR), a target enzyme for chemotherapy against Chagas disease, was also studied. Six BBIQ alkaloids (antioquine, cepharanthine, daphnoline, limacine, cycleanine and (-) curine) displayed a 50$ of less than 100 microM. Daphnoline and curine, with LC50 values of 10 microM, are attractive for further investigation as potential anti-Chagasic drugs. Kinetic analyses suggested the BBIQ alkaloids are mixed inhibitors of TR. These compounds are reasonably potent inhibitors of TR ; the best TR inhibitor, cepharanthine, had an IC50 of 15 microM, which is the same order of magnitude as its LC50 against #T. cruzi$. The similar magnitudes of the IC50 and LC50 values suggest that inhibition of TR could contribute to the trypanocidal activity exhibited by the BBIQ alkaloids. (Résumé d'auteur

Acetogenins and other compounds from Rollinia emarginata and their antiprotozoal activities

Bioactivity-directed fractionation of the MeOH extract of the stem barks of #Rollinia emarginata$ resulted in the isolation of six compounds, four acetogenins, rolliniastatin-1, sylvaticin, squamocin, and rollidecin B, one lignan, lirioresinol B, and an oxoaporphine, liriodenin. Their structures were determined by spectroscopic analysis and their in vitro leishmanicidal and trypanocidal properties are reported. (Résumé d'auteur

New prenylated quinones from Peperomia galioides

Two new prenylated quinones, piperogalone and galopiperone, and a new prenylated dihydroquinone, hydropiperone, were isolated from #Peperomia galioides H.B.K (#Piperaceae). Hydropiperone exhibited potent antiparasitic activity against three species of #Leishmania$. (Résumé d'auteur