RESUMEN
ABSTRACT Leishmania infantum is an etiologic agent of visceral leishmaniasis. This disease is a neglected disease that can be fatal if not treated and additionally, the few therapeutic option present several drawbacks, including difficult route of administration and toxicity, which turn the search for new therapeutic alternatives necessary. Herein, we evaluated the leishmanicidal in vitro activity of the solanum extract from Solanum lycocarpum A. St.-Hil., Solanaceae, and the isolated alkaloids solasodine, solamargine and solasonine against promastigotes and intracellular amastigotes of L. infantum. Solasodine (IC50-pro = 4.7 µg/ml; IC50-ama = 10.8 µg/ml) and solamargine (IC50-pro = 8.1 µg/ml; IC50-ama = 3.0 µg/ml) exhibited interesting leishmanicidal ativity. Solasonine was approximately four-times (Selective Index 3.7) more selective to the parasite than to the host cells. This data suggest that solasonine might be considered as a potential drug candidate for leishmaniasis treatment.
RESUMEN
N-oxide derivatives compounds such as furoxan and benzofuroxan are promising scaffolds for designing of new antileishmanial drugs. A series of furoxan (1,2,5-oxadiazole 2-N-oxide) (compounds 4a-b, and 14a-f) and benzofuroxan (benzo[c][1,2,5]oxadiazole1-N-oxide) (compounds 8a-c) derivatives were evaluated against in vitro cultured L. infantum promastigotes and amastigotes. The compounds exhibited activity against promastigote and intracellular amastigote forms with EC50 values ranging from 2.9 to 71.2µM and 2.1 to 18.2µM, respectively. The most promising compound, 14e, showed good antileishmanial activity (EC50=3.1µM) against intracellular amastigote forms of L. infantum with a selectivity index, based on murine macrophages (SI=66.4), almost 3-times superior to that presented by the standard drug amphotericin B (AmpB). The efficacy of 14e to eliminate the parasites in vivo was also demonstrated. Treatment of L. infantum-infected hamsters with compound 14e at 3.0mg/Kg/day led to a meaningful reduction of parasite load in spleen (49.9%) and liver (54.2%), respectively; these data were corroborated by histopathological analysis, which also revealed reduction in the number of inflammatory cells in the liver of the treated animals. Moreover, histological analysis of the spleen and kidney of treated animals did not reveal alterations suggestive of toxic effects. The parasite load reduction might be related to NO production, since this molecule is a NO-donor. We observed neither side effects nor elevation of hepatic/renal biomarker levels in the plasma. The data herein presented suggest that the compound should be considered in the development of new drugs for treatment of visceral leishmaniasis.
Asunto(s)
Antiprotozoarios/uso terapéutico , Benzoxazoles/uso terapéutico , Leishmania infantum/efectos de los fármacos , Leishmaniasis Visceral/tratamiento farmacológico , Anfotericina B/farmacología , Anfotericina B/uso terapéutico , Anfotericina B/toxicidad , Animales , Antiprotozoarios/química , Antiprotozoarios/farmacología , Benzoxazoles/química , Benzoxazoles/farmacología , Benzoxazoles/toxicidad , Biomarcadores/metabolismo , Cricetinae , Riñón/efectos de los fármacos , Riñón/parasitología , Riñón/patología , Riñón/fisiopatología , Leishmaniasis Visceral/parasitología , Hígado/efectos de los fármacos , Hígado/parasitología , Hígado/patología , Hígado/fisiopatología , Macrófagos/efectos de los fármacos , Macrófagos/parasitología , Macrófagos/patología , Masculino , Ratones , Óxido Nítrico/biosíntesis , Bazo/efectos de los fármacos , Bazo/parasitología , Bazo/patología , Resultado del TratamientoRESUMEN
Leishmaniasis is a disease found throughout the (sub)tropical parts of the world caused by protozoan parasites of the Leishmania genus. Despite the numerous problems associated with existing treatments, pharmaceutical companies continue to neglect the development of better ones. The high toxicity of current drugs combined with emerging resistance makes the discovery of new therapeutic alternatives urgent. We report here the evaluation of a binuclear cyclopalladated complex containing Pd(II) and N,N'-dimethylbenzylamine (Hdmba) against Leishmania amazonensis The compound [Pd(dmba)(µ-N3)]2 (CP2) inhibits promastigote growth (50% inhibitory concentration [IC50] = 13.2 ± 0.7 µM) and decreases the proliferation of intracellular amastigotes in in vitro incubated macrophages (IC50 = 10.2 ± 2.2 µM) without a cytotoxic effect when tested against peritoneal macrophages (50% cytotoxic concentration = 506.0 ± 10.7 µM). In addition, CP2 was also active against T. cruzi intracellular amastigotes (IC50 = 2.3 ± 0.5 µM, selective index = 225), an indication of its potential for use in Chagas disease therapy. In vivo assays using L. amazonensis-infected BALB/c showed an 80% reduction in parasite load compared to infected and nontreated animals. Also, compared to amphotericin B treatment, CP2 did not show any side effects, which was corroborated by the analysis of plasma levels of different hepatic and renal biomarkers. Furthermore, CP2 was able to inhibit Leishmania donovani topoisomerase 1B (Ldtopo1B), a potentially important target in this parasite. (This study has been registered at ClinicalTrials.gov under identifier NCT02169141.).
Asunto(s)
Antiprotozoarios/uso terapéutico , Bencilaminas/uso terapéutico , Leishmania mexicana/efectos de los fármacos , Leishmaniasis Cutánea/tratamiento farmacológico , Paladio/uso terapéutico , Inhibidores de Topoisomerasa I/uso terapéutico , Anfotericina B/uso terapéutico , Animales , Antiprotozoarios/efectos adversos , Bencilaminas/química , Dominio Catalítico/efectos de los fármacos , Células Cultivadas , ADN-Topoisomerasas de Tipo I/efectos de los fármacos , Modelos Animales de Enfermedad , Pruebas de Función Renal , Leishmania mexicana/crecimiento & desarrollo , Pruebas de Función Hepática , Macrófagos Peritoneales/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos BALB C , Enfermedades Desatendidas/tratamiento farmacológico , Enfermedades Desatendidas/parasitología , Paladio/química , Carga de Parásitos , Pruebas de Sensibilidad ParasitariaRESUMEN
Chalcones form a class of compounds that belong to the flavonoid family and are widely distributed in plants. Their simple structure and the ease of preparation make chalcones attractive scaffolds for the synthesis of a large number of derivatives enabling the evaluation of the effects of different functional groups on biological activities. In this Letter, we report the successful synthesis of a series of novel prenylated chalcones via Claisen-Schmidt condensation and the evaluation of their effect on the viability of the Trypanosomatidae parasites Leishmania amazonensis, Leishmania infantum and Trypanosoma cruzi.
Asunto(s)
Chalcona/síntesis química , Chalcona/farmacología , Leishmania infantum/efectos de los fármacos , Trypanosoma cruzi/efectos de los fármacos , Chalcona/química , Concentración 50 Inhibidora , Prenilación , Relación Estructura-Actividad , Tripanocidas/síntesis química , Tripanocidas/química , Tripanocidas/farmacologíaRESUMEN
Four interconverting flavanone glycosides [(2R)- and (2S)-3',4',5,6-tetrahydroxyflavanone 7-O-ß-D-glucopyranoside, and (2R)- and (2S)-3',4',5,8-tetrahydroxyflavanone 7-O-ß-D-glucopyranoside], in addition to eight known flavonoids [naringenin, asebogenin, sakuranetin, 6-hydroxyluteolin 7-O-ß-D-glucoside, (2R)- and (2S)-eriodictyol 7-O-ß-D-glucopyranoside, aromadendrin and phloretin], three phenylpropanoid glycosides [forsythoside B, alyssonoside and verbascoside] and the epoxylignan lariciresinol 4'-O-ß-D-glucopyranoside were isolated and identified in the EtOH extract of the aerial parts of Lippia salviaefolia Cham. The phytochemical study herein was guided by preliminary antioxidant tests, namely, ß-carotene protection and 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging activity. The crude extracts, their active fractions and the isolated compounds were assayed against intracellular reactive oxygen species (ROS) and human embryonic kidney HEK-293 and human melanoma M14 cancer cell growth. Aromadendrin and phloretin were able to counteract elevation of ROS induced by the oxidant t-butylhydroperoxide (t-BOOH) in HEK-293 cells, whereas phloretin strongly protected HEK-293 cells from ROS damage at 1 µM. Additionally, phloretin exhibited a significant growth inhibitory effect at 20-40 µM in both HEK-293 and M14 cells and induced a concentration dependent apoptosis at 20 µM in M14 cells, suggesting a selective action towards malignant cells. Due to their equilibria, the four interconverting flavanone glycosides were studied using 1D and 2D NMR, HPLC-CD-PDA and HRMS analyses.