RESUMEN
BACKGROUND: Curry powder is a blend of spices that is extensively consumed worldwide and mainly in Central Asia. Its preparation is strictly related to each locality and, because of the health benefits of its constituents, eight commercial forms of this condiment were biologically and chemically investigated. This study aimed to compare their chemical profile as well as their anti-inflammatory, cytotoxic, and antiparasitic activities. RESULTS: Curry samples 1 and 7 inhibited leukocyte influx and myeloperoxidase activity, while only 7 was active on protein exudate and NOx species. 2, 6, and 8 displayed trypanocidal effect against Trypanosoma cruzi amastigote, whereas 6 showed antileishmanial activity on Leishmania amazonensis amastigote. 2, 6, and 8 also inhibited the growth of THP-1 cells used as the parasite's host. Among the cytotoxic samples (4 and 6), curry sample 6 induced apoptosis in MDA-MB-231 cells. Nevertheless, 4 and 6 were unselectively cytotoxic to non-tumoral and tumoral cells. The anti-inflammatory, cytotoxicity, and antiparasitic assays were respectively performed by carrageenan-induced pleurisy test, Alamar blue assay, and intracellular parasite-host cell model. Ultra-performance liquid chromatographic-electrospray ionization mass spectrometric data from the spices revealed both similar and different metabolites in their composition. CONCLUSION: The results obtained indicate that different formulations can contribute different health benefits as a result of their chemical composition. © 2018 Society of Chemical Industry.
Asunto(s)
Antiinflamatorios/química , Antiinflamatorios/farmacología , Antiprotozoarios/química , Antiprotozoarios/farmacología , Extractos Vegetales/química , Extractos Vegetales/farmacología , Especias/análisis , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Cromatografía Líquida de Alta Presión , Humanos , Leishmania/efectos de los fármacos , Leishmania/crecimiento & desarrollo , Pleuresia/tratamiento farmacológico , Pleuresia/inmunología , Polvos/química , Espectrometría de Masa por Ionización de Electrospray , Trypanosoma cruzi/efectos de los fármacos , Trypanosoma cruzi/crecimiento & desarrolloRESUMEN
Despite the impressive scientific and technological advances of recent decades, no effective treatment is currently available for Chagas disease. Our research group has been studying the design and synthesis of analogues of natural lignans aiming to identify compounds with antiparasitic activity. This article reports the synthesis of 42 novel bis-heterocyclic derivatives and the structure-activity relationship study conducted based on results of biological assays against Trypanosoma cruzi amastigotes. Thirty-seven compounds were active, and eight of them had GI50 values lower than 100⯵M (GI50 88.4-12.2⯵M). A qualitative structure activity relationship study using three dimensional descriptors was carried out and showed a correlation between growth inhibitory potency and the presence of bulky hydrophobic groups located at rings A and D of the compounds. Compound 3-(3,4-dimethoxyphenyl)-5-((4-(4-pentylphenyl)-1H-1,2,3-triazol-1-yl)methyl)isoxazole (31) was the most active in the series (GI50 12.2⯵M), showing, in vitro, low toxicity and potency similar to benznidazole (GI50 10.2⯵M). These results suggest that this compound can be a promising scaffold for the design of new trypanocidal compounds.
Asunto(s)
Antiprotozoarios/síntesis química , Antiprotozoarios/farmacología , Leishmania/efectos de los fármacos , Lignanos/química , Trypanosoma cruzi/efectos de los fármacos , Antiprotozoarios/química , Espectroscopía de Resonancia Magnética con Carbono-13 , Evaluación Preclínica de Medicamentos , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/farmacología , Humanos , Isoxazoles/síntesis química , Isoxazoles/química , Isoxazoles/farmacología , NADH NADPH Oxidorreductasas/antagonistas & inhibidores , Espectroscopía de Protones por Resonancia Magnética , Espectrofotometría Infrarroja , Relación Estructura-Actividad , Células THP-1 , Triazoles/síntesis química , Triazoles/química , Triazoles/farmacologíaRESUMEN
Different studies reported that genetic predisposition or metabolic dysfunction are the risk factors for cancer. Infectious parasitic diseases were listed among factors that predispose to cancer. Because of the resemblance between the life cycle of cancer cells and some parasites, this study aimed to prepare pyran derivatives with cytotoxic and antiprotozoal potencies. Therefore, 7 chromenes, 10 pyranocoumarins, and an unexpected intermediate were obtained from a multi-reagent one-pot reaction. These compounds were evaluated for their cytotoxicity on sensitive and resistant leukemia cancer cells lines and against two protozoan parasites, namely Trypanosoma cruzi and Leishmania amazonensis amastigote. Promising cytotoxicity (IC50 values of less than 1 µM) was obtained for two of the synthetic products (12 and 15). Compound 12 induced apoptosis and cell cycle arrest in CCRF-CEM leukemia cells in G0/G1 while compound 15 and doxorubicin induced apoptosis and arrest in the S and G2/M phases. Ten of these products showed trypanocidal activity, while only five of them were weakly active on L. amazonensis. Three of the obtained pyrans showed significant cytotoxicity and antitrypanocidal activity, simultaneously. Nevertheless, all antiparasitic compounds revealed potency with low selectivity toward THP-1 cells used as host.
Asunto(s)
Antineoplásicos/farmacología , Antiprotozoarios/farmacología , Benzopiranos/farmacología , Leishmania/efectos de los fármacos , Trypanosoma cruzi/efectos de los fármacos , Antineoplásicos/síntesis química , Antineoplásicos/química , Antiprotozoarios/síntesis química , Antiprotozoarios/química , Apoptosis/efectos de los fármacos , Benzopiranos/química , Puntos de Control del Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Pruebas de Sensibilidad Parasitaria , Relación Estructura-Actividad , Células THP-1 , Células Tumorales CultivadasRESUMEN
INTRODUCTION: The resin of Cola nitida is used in western Cameroon as incense for spiritual protection and during ritual ceremonies. This plant secretion has never been investigated although previous chemical and biological studies on other resins have drawn many attentions. OBJECTIVE: The resin fractions which revealed inhibitory effect on nitric oxide (NO) and tumour necrosis factor alpha (TNF-α) released by lipopolysaccharide (LPS)-activated J774 macrophage as well as on intracellular forms of Leishmania amazonensis and Trypanosoma cruzi amastigote were chemically characterised. Moreover, their antiparasitic activities were compared to those of semi-synthetic triterpenes. METHODOLOGY: The anti-inflammatory activity was evaluated by measuring the nitrite production and the TNF-α concentration in the supernatants of LPS-activated macrophages by antigen capture enzyme-linked immunosorbent assay. Moreover, the antiparasitic assay was performed by infecting the host cells (THP-1) in a ratio parasite/cell 10:1 (L. amazonensis) and 2:1 (T. cruzi) and then exposed to the samples. The resin was separated in vacuo by liquid chromatography because of its sticky behaviour and the chemical profiles of the obtained fractions (F1-F4) were established by dereplication based on UPLC-ESI-MS2 data while semi-synthetic triterpenes were prepared from α-amyrin by oxidation reactions. RESULTS: Fractions F1-F4 inhibited NO and TNF-α almost similarly. However, only F1, F3 and F4 showed promising antiparasitic activities while F2 was moderately active against both parasites. Hence, F1-F4 were exclusively composed of pentacyclic triterpenes bearing oleanane and ursane skeletons. Semi-synthetic compounds revealed no to moderate antiparasitic activity compared to the fractions. CONCLUSION: Although it will be difficult to prove the interaction resin-spirit, interesting bioactivities were found in the resin fractions.
Asunto(s)
Cromatografía Liquida/métodos , Cola/química , Leishmania/efectos de los fármacos , Macrófagos/efectos de los fármacos , Espectrometría de Masas/métodos , Trypanosoma cruzi/efectos de los fármacos , Animales , Línea Celular , Regulación de la Expresión Génica/efectos de los fármacos , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Lipopolisacáridos/farmacología , Ratones , Óxido Nítrico/metabolismo , Extractos Vegetales/química , Extractos Vegetales/farmacología , Resinas de Plantas/química , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Drugs containing the1,4-dihydropyridine (DHP) core have recently attracted attention concerning their antiparasitic effect against various species of Leishmania and Trypanosoma. This approach named drugs repositioning led to interesting results, which have prompted us to prepare 21 DHP's analogues. The 1,4-DHP scaffold was decorated with different function groups at tree points including the nitrogen atom (NH and N-phenyl), the aryl group attached to C-4 (various substituted aryl residues) and the carbon atoms 2 and 6 (bearing Ph or Me groups). Moreover, the products were evaluated for their cytotoxicity on three cancer and a non-tumoral cell lines. Only 6 of them were antiproliferative and their weak effect (CC50 comprised between 27 and 98µM) suggested these DHPs as good candidates against the intracellular amastigote forms of L. amazonensis and T. cruzi. L. amazonensis was sensitive to DHPs 5, 11 and 15 (IC50 values at 15.11, 45.70 and 53.13µM, respectively) while 12 of them displayed significant to moderate trypanocidal activities against T. cruzi. The best trypanocidal activities were obtained with compounds 2, 18 and 21 showing IC50 values at 4.95, 5.44, and 6.64µM, respectively. A part of the N-phenylated DHPs showed a better selectivity than their NH analogues towards THP-1 cells. 4-Chlorophenyl, 4-nitrophenyl and 3-nitrophenyl residues attached to the carbon atom 4 turned to be important sub-structures for the antitrypanosomal activity.
Asunto(s)
Bloqueadores de los Canales de Calcio/farmacología , Leishmania mexicana/efectos de los fármacos , Tripanocidas/farmacología , Trypanosoma cruzi/efectos de los fármacos , Animales , Bloqueadores de los Canales de Calcio/síntesis química , Línea Celular , Línea Celular Tumoral , Dihidropiridinas , Humanos , Células MCF-7 , Ratones , Células 3T3 NIH , Relación Estructura-Actividad , Tripanocidas/síntesis químicaRESUMEN
Leishmanicidal and trypanocidal activity of seventeen lipophilic diamines was evaluated in vitro against Leishmania braziliensis, L. chagasi, and Trypanosoma cruzi. Twelve compounds presented anti-Leishmania and six showed anti-T. cruzi amastigote activity. Compound 14 (N-tetradecyl-1,4-butanediamine) was the most active against both L. braziliensis (IC50 = 2.6 µm) and L. chagasi (IC50 = 3.0 µm) which showed a selectivity index (SI) >100. N-decyl-1,6-hexanediamine (compound 9) presented an IC50 = 1.6 µm and SI >187 and was over six times more potent than the reference drug benznidazole against T. cruzi. Treatment of infected or uninfected macrophages with compounds 9 and 14 did not induce significant TNFα and NO production. Four compounds (15, 16, 22, and 23) inhibited 78.9%, 77.7%, 83.7%, and 70.1% of rTRLb activity, respectively, and compound 23 inhibited 73.3% of rTRTc activity at 100 µm. A concentration-dependent effect on mitochondrial membrane depolarization was observed in T. cruzi epimastigotes treated with compound 9, suggesting this mechanism may be involved in the trypanocidal effect. On the contrary, in L. braziliensis promastigotes treated with compound 14, no mitochondrial depolarization was observed. Our results demonstrate that N-decyl-1,6-hexanediamine and N-tetradecyl-1,4-butanediamine are promising molecules for the development of novel leading compounds against T. cruzi and Leishmania spp., particularly given a possible alternative mechanism of action.
Asunto(s)
Diaminas/farmacología , Leishmania/efectos de los fármacos , Tripanocidas/farmacología , Trypanosoma cruzi/efectos de los fármacos , Animales , Células de la Médula Ósea/citología , Supervivencia Celular/efectos de los fármacos , Diaminas/química , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Macrófagos/parasitología , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Ratones Endogámicos BALB C , Óxido Nítrico/metabolismo , Tripanocidas/química , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
BACKGROUND: American Trypanosomiasis or Chagas disease is caused by Trypanosoma cruzi which currently infects approximately 16 million people in the Americas causing high morbidity and mortality. Diagnosis of American trypanosomiasis relies on serology, primarily using indirect immunofluorescence assay (IFA) with T. cruzi epimastigote forms. The closely related but nonpathogenic Trypanosoma rangeli has a sympatric distribution with T. cruzi and is carried by the same vectors. As a result false positives are frequently generated. This confounding factor leads to increased diagnostic test costs and where false positives are not caught, endangers human health due to the toxicity of the drugs used to treat Chagas disease. RESULTS: In the present study, serologic cross-reactivity between the two species was compared for the currently used epimastigote form and the more pathologically relevant trypomastigote form, using IFA and immunoblotting (IB) assays. Our results reveal an important decrease in cross reactivity when T. rangeli culture-derived trypomastigotes are used in IFA based diagnosis of Chagas disease. Western blot results using sera from both acute and chronic chagasic patients presenting with cardiac, indeterminate or digestive disease revealed similar, but not identical, antigenic profiles. CONCLUSION: This is the first study addressing the serological cross-reactivity between distinct forms and strains of T. rangeli and T. cruzi using sera from distinct phases of the Chagasic infection. Several T. rangeli-specific proteins were detected, which may have potential as diagnostic tools.