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1.
Chem Biodivers ; 20(7): e202300523, 2023 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-37263974

RESUMEN

Leishmaniasis is a tropical zoonotic disease. It is found in 98 countries, with an estimated 1.3 million people being affected annually. During the life cycle, the Leishmania parasite alternates between promastigote and amastigote forms. The first line treatment for leishmaniasis are the pentavalent antimonials, such as N-methylglucamine antimoniate (Glucantime®) and sodium stibogluconate (Pentostam®). These drugs are commonly related to be associated with dangerous side effects such as cardiotoxicity, nephrotoxicity, hepatotoxicity, and pancreatitis. Considering these aspects, this work aimed to obtain a new series of limonene-acylthiosemicarbazides hybrids as an alternative for the treatment of leishmaniasis. For this, promastigotes, axenic amastigotes, and intracellular amastigotes of Leishmania amazonensis were used in the antiproliferative assay; J774-A1 macrophages for the cytotoxicity assay; and electron microscopy techniques were performed to analyze the morphology and ultrastructure of parasites. ATZ-S-04 compound showed the best result in both tests. Its IC50 , in promastigotes, axenic amastigotes and intracellular amastigotes was 0.35±0.08 µM, 0.49±0.06 µM, and 15.90±2.88 µM, respectively. Cytotoxicity assay determined a CC50 of 16.10±1.76 µM for the same compound. By electron microscopy, it was observed that ATZ-S-04 affected mainly the Golgi complex, in addition to morphological changes in promastigote forms of L. amazonensis.


Asunto(s)
Antiprotozoarios , Leishmania , Leishmaniasis , Humanos , Animales , Ratones , Limoneno/farmacología , Antiprotozoarios/farmacología , Antiprotozoarios/química , Leishmaniasis/parasitología , Macrófagos , Antimoniato de Meglumina/farmacología , Ratones Endogámicos BALB C
2.
Front Microbiol ; 8: 255, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28270805

RESUMEN

Drug combination therapy is a current trend to treat complex diseases. Many benefits are expected from this strategy, such as cytotoxicity decrease, retardation of resistant strains development, and activity increment. This study evaluated in vitro combination between an innovative thiosemicarbazone molecule - BZTS with miltefosine, a drug already consolidated in the leishmaniasis treatment, against Leishmania amazonensis. Cytotoxicity effects were also evaluated on macrophages and erythrocytes. Synergistic antileishmania effect and antagonist cytotoxicity were revealed from this combination therapy. Mechanisms of action assays were performed in order to investigate the main cell pathways induced by this treatment. Mitochondrial dysfunction generated a significant increase of reactive oxygen and nitrogen species production, causing severe cell injuries and promoting intense autophagy process and consequent apoptosis cell death. However, this phenomenon was not strong enough to promote dead in mammalian cell, providing the potential selective effect of the tested combination for the protozoa. Thus, the results confirmed that drugs involved in distinct metabolic routes are promising agents for drug combination therapy, promoting a synergistic effect.

3.
Microbes Infect ; 18(12): 787-797, 2016 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-27484335

RESUMEN

This work evaluated the in vitro and in vivo activity of TDZ 2 on Trypanosoma cruzi amastigotes and determined the possible mechanism of action of this compound on T. cruzi death. TDZ 2 inhibited T. cruzi proliferation in vitro and had low haemolytic potential. It also induced morphological and ultrastructural alterations. We observed a reduction of cell volume, the depolarization of the mitochondrial membrane, an increase in ROS production, lipoperoxidation of the cell membrane, lipid bodies formation and production of nitric oxide, a decrease in reduced thiols levels and, presence of autophagic vacuoles. The in vivo study found a reduction of parasitemia in animals treated with TDZ 2 alone or combined with benznidazole. Altogether, the alterations induced by TDZ 2 point to an oxidative stress condition that lead to T. cruzi cell death.


Asunto(s)
Antiprotozoarios/farmacología , Benzaldehídos/farmacología , Ciclohexenos/farmacología , Estrés Oxidativo , Terpenos/farmacología , Tiadiazoles/farmacología , Tiosemicarbazonas/farmacología , Trypanosoma cruzi/efectos de los fármacos , Animales , Antiprotozoarios/química , Benzaldehídos/química , Enfermedad de Chagas/tratamiento farmacológico , Enfermedad de Chagas/parasitología , Ciclohexenos/química , Modelos Animales de Enfermedad , Femenino , Humanos , Limoneno , Ratones Endogámicos BALB C , Estructura Molecular , Carga de Parásitos , Parasitemia/tratamiento farmacológico , Parasitemia/parasitología , Terpenos/química , Tiadiazoles/química , Tiosemicarbazonas/química , Resultado del Tratamiento , Trypanosoma cruzi/crecimiento & desarrollo , Trypanosoma cruzi/fisiología , Trypanosoma cruzi/ultraestructura
4.
Parasitology ; 142(7): 978-88, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-25711881

RESUMEN

Trypanosoma cruzi is the causative agent of Chagas' disease, a parasitic disease that remains a serious health concern with unsatisfactory treatment. Drugs that are currently used to treat Chagas' disease are partially effective in the acute phase but ineffective in the chronic phase of the disease. The aim of the present study was to evaluate the antitrypanosomal activity and morphological, ultrastructural and biochemical alterations induced by a new molecule, 4-nitrobenzaldehyde thiosemicarbazone (BZTS), derived from S-(-)-limonene against epimastigote, trypomastigote and intracellular amastigote forms of T. cruzi. BZTS inhibited the growth of epimastigotes (IC50 = 9·2 µ m), intracellular amastigotes (IC50 = 3·23 µ m) and inhibited the viability of trypomastigotes (EC50 = 1·43 µ m). BZTS had a CC50 of 37·45 µ m in LLCMK2 cells. BZTS induced rounding and distortion of the cell body and severely damaged parasite mitochondria, reflected by extensive swelling and disorganization in the inner mitochondrial membrane and the presence of concentric membrane structures inside the organelle. Cytoplasmic vacuolization, endoplasmic reticulum that surrounded organelles, the loss of mitochondrial membrane potential, and increased mitochondrial O2 •- production were also observed. Our results suggest that BZTS alters the ultrastructure and physiology of mitochondria, which could be closely related to parasite death.


Asunto(s)
Ciclohexenos/química , Estadios del Ciclo de Vida/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Terpenos/química , Tripanocidas/farmacología , Trypanosoma cruzi/efectos de los fármacos , Animales , Benzaldehídos/química , Benzaldehídos/farmacología , Línea Celular , Retículo Endoplásmico/efectos de los fármacos , Retículo Endoplásmico/patología , Retículo Endoplásmico/ultraestructura , Células Epiteliales/efectos de los fármacos , Células Epiteliales/parasitología , Estadios del Ciclo de Vida/fisiología , Limoneno , Macaca mulatta , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mitocondrias/metabolismo , Mitocondrias/patología , Mitocondrias/ultraestructura , Superóxidos/agonistas , Superóxidos/metabolismo , Tiosemicarbazonas/química , Tiosemicarbazonas/farmacología , Tripanocidas/química , Trypanosoma cruzi/crecimiento & desarrollo , Trypanosoma cruzi/metabolismo , Trypanosoma cruzi/ultraestructura
5.
BMC Microbiol ; 14: 236, 2014 Sep 26.
Artículo en Inglés | MEDLINE | ID: mdl-25253283

RESUMEN

BACKGROUND: The treatment of leishmaniasis with pentavalent antimonials is problematic because of their toxicity. Investigations of potentially active molecules are important to discover less toxic drugs that are viable economic alternatives for the treatment of leishmaniasis. Thiosemicarbazones are a group of molecules that are known for their wide versatility and biological activity. In the present study, we examined the antileishmania activity, mechanism of action, and biochemical alterations produced by a novel molecule, 4-nitrobenzaldehyde thiosemicarbazone (BZTS), derived from S-limonene against Leishmania amazonensis. RESULTS: BZTS inhibited the growth of the promastigote and axenic amastigote forms, with an IC50 of 3.8 and 8.0 µM, respectively. Intracellular amastigotes were inhibited by the compound with an IC50 of 7.7 µM. BZTS also had a CC50 of 88.8 µM for the macrophage strain J774A1. BZTS altered the shape, size, and ultrastructure of the parasites, including damage to mitochondria, reflected by extensive swelling and disorganization of the inner mitochondrial membrane, intense cytoplasmic vacuolization, and the presence of concentric membrane structures inside the organelle. Cytoplasmic lipid bodies, vesicles inside vacuoles in the flagellar pocket, and enlargement were also observed. BZTS did not induce alterations in the plasma membrane or increase annexin-V fluorescence intensity, indicating no phosphatidylserine exposure. However, it induced the production of mitochondrial superoxide anion radicals. CONCLUSIONS: The present results indicate that BZTS induced dramatic effects on the ultrastructure of L. amazonensis, which might be associated with mitochondrial dysfunction and oxidative damage, leading to parasite death.


Asunto(s)
Antiprotozoarios/farmacología , Benzaldehídos/farmacología , Ciclohexenos/química , Leishmania mexicana/efectos de los fármacos , Terpenos/química , Tiosemicarbazonas/farmacología , Animales , Antiprotozoarios/química , Antiprotozoarios/aislamiento & purificación , Benzaldehídos/aislamiento & purificación , Muerte Celular , Línea Celular , Supervivencia Celular/efectos de los fármacos , Concentración 50 Inhibidora , Leishmania mexicana/crecimiento & desarrollo , Leishmania mexicana/ultraestructura , Limoneno , Macrófagos/efectos de los fármacos , Ratones , Orgánulos/efectos de los fármacos , Orgánulos/ultraestructura , Pruebas de Sensibilidad Parasitaria , Tiosemicarbazonas/aislamiento & purificación
6.
Eur J Med Chem ; 79: 110-6, 2014 May 22.
Artículo en Inglés | MEDLINE | ID: mdl-24727464

RESUMEN

In an attempt to develop potent and selective antitumor agents, a series of novel thiosemicarbazones derived from a natural monoterpene R-(+)-limonene was synthesized and their antitumor activity was evaluated. Overall, the majority of tested compounds exhibited considerable inhibitory effects on the growth of a wide range of cancer cell lines. Almost all of tested thiosemicarbazones were especially sensitive to prostate cells (PC-3). Derivatives 5, 6, 8, 9, 10, 11 and 13 presented the most potent antitumor activity against PC-3 cells. These compounds showed lower value of GI50 (0.04-0.05 µM) than the reference drug paclitaxel, besides a high selectivity for the same cell line. The 4-fluorobenzaldehyde derivative 10 was the most selective compound for prostate cells, while 2-hydroxybenzaldehyde derivative 8 was the most active compound, with potent antitumor activity against all tested cell lines.


Asunto(s)
Antineoplásicos/farmacología , Ciclohexenos/química , Terpenos/química , Tiosemicarbazonas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Células K562 , Limoneno , Células MCF-7 , Estructura Molecular , Estereoisomerismo , Relación Estructura-Actividad , Tiosemicarbazonas/síntesis química , Tiosemicarbazonas/química
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