Glibenclamide, a Blocker of K(+)(ATP) Channels, Shows Antileishmanial Activity in Experimental Murine Cutaneous Leishmaniasis

Glibenclamide reduced the rate of lesion growth in BALB/c mice infected with Leishmania (Leishmania) mexicana, the effect was dose dependent, and the highest dose proved more effective than glucantime. Cross-resistance to glucantime was found in animals infected with a glibenclamide-resistant line, but combined therapy reduced lesion progression even in the glibenclamide-resistant strain

Amiodarone Destabilizes Intracellular Ca2+ Homeostasis and Biosynthesis of Sterols in Leishmania mexicana▿

Leishmaniasis represents a serious public health problem worldwide. The first line of treatment is based on glucantime and pentostan, which generate toxic effects in treated patients. We have recently shown that amiodarone, frequently used as an antiarrhythmic, possesses activity against Trypanosoma cruzi through the disruption of mitochondrial Ca2+ homeostasis and the inhibition of parasite ergosterol biosynthesis, specifically at the level of oxidosqualene cyclase activity (G. Benaim, J. Sanders, Y. Garcia-Marchan, C. Colina, R. Lira, A. Caldera, G. Payares, C. Sanoja, J. Burgos, A. Leon-Rossell, J. Concepcion, A. Schijman, M. Levin, E. Oldfield, and J. Urbina, J. Med. Chem. 49:892-899, 2006). Here we show that at therapeutic concentrations, amiodarone has a profound effect on the viability of Leishmania mexicana promastigotes. Additionally, its effect on the viability of the parasite was greater against intracellular amastigotes than against promastigotes, and it did not affect the host cell. Using fluorimetric and confocal microscopy techniques, we also demonstrated that the mechanism of action of amiodarone was related to the disruption of intracellular Ca2+ homeostasis through a direct action not only on the mitochondria but also on the acidocalcisomes. On the other hand, analysis of the free sterols in promastigotes incubated with amiodarone showed that this drug also affected the biosynthesis of 5-dehydroepisterol, which results in squalene accumulation, thus suggesting that amiodarone inhibits the squalene epoxidase activity of the parasite. Taken together, the results obtained in the present work point to a more general effect of amiodarone in trypanosomatids, opening potential therapeutic possibilities for this infectious disease

Synthesis and biological evaluation of benzothiazole-6-carbohydrazide derivatives as antiparasitic agents

A series of N´-substituted-2-(5-nitrofuran or 5-nitrothiophen-2-yl)-3h-benzo[d]thiazole-6-carbohydrazide derivatives were synthesized and investigated for their abilities to inhibit B-hematin formation, hemoglobin proteolysis and for their antimalarial efficacy in rodent Plasmodium berghei. Moreover, we investigated the effect on the viability of Trypanosoma cruzi and Leishmania braziliensis in vitro. We performed a scan to evaluate the cytotoxic effects against two non tumourogenic cell lines. We found that compounds 5a, 6a, and 6g were the most promising as inhibitors of B-hematin formation, especial attention should be paid to 6a which also inhibited hemoglobin proteolysis moderately, decreased parasitaemia and prolonged survivals in infected-mice significantly compared to vehicle controls. Finally, we demonstrated that the compound 7f have a profound effect on the viability of T. cruzi (Tulahuen, CL Brener), shown an IC50 values of 7.7 μm and 0.2 μm respectively, without affecting the viability of the host cells. All compounds showed a marginal activity against L. braziliensis. Thus, compounds 6a and 7f showed anti-parasitic efficacy and good safety inde

Anti-leishmanial evaluation of C2-aryl quinolines: Mechanistic insight on bioenergetics and sterol biosynthetic pathway of Leishmania braziliensis

A series of diverse simple C2-aryl quinolines was synthesized de novo via a straightforward synthesis based on the acid-catalyzed multicomponent imino Diels–Alder reactions. Seven selected quinolines were evaluated at different stages of Leishmania braziliensis parasite. Among them, the 6-ethyl-2-phenylquinoline 5f was able to inhibit the growth of promastigotes of this parasite without affecting the mammalian cells viability and decreasing the number of intracellular L. braziliensis amastigotes on BMDM macrophages. The mechanism of action studied for the selected compound consisted in: (1) alteration of parasite bioenergetics, by disrupting mitochondrial electrochemical potential and alkalinisation of acidocalcisomes, and (2) inhibition of ergosterol biosynthetic pathway in promastigote forms. These results validate the efficiency of quinoline molecules as leishmanicide compounds.Departamento Administrativo de Ciencia, Tecnología e Innovación [CO] Colciencias5507-543-31904Programa: Bioprospección y desarrollo de ingredientes naturales para las industrias cosmética, farmacéutica y de productos de aseo con base en la biodiversidad colombianan

Efectos deletereos del Jc25 sobre la bioenergética celular y la biosíntesis de esteroles de Leishmania braziliensis

La Leishmaniasis es considerada por la oMS como una de las seis parasitosis con mayores indices de morbilidad y mortalidada nivel mundial. Las drogas de primera linea utilizadas (GlucantimeR y PentostanR) generan graves efectos secundarios,asi como fenomenos de quimioresistencia. En este sentido, nuestro grupo de investigacion se planteo el reto de desarrollary sintetizar nuevos compuestos antiparasitarios efectivos. bajo metodologias de sintesis rapidas y economicas, logramosobtener 14 compuestos derivados de benzimidazoles. Con la finalidad de evaluar el potencial antiparasitario, se realizaroncurvas de crecimiento evaluando diversas concentraciones de los compuestos. Demostramos que uno de los derivados(jC25), disminuyo la viabilidad de promastigotes de L. braziliensis de manera dependiente de la dosis, con un valor de iC50:56ƒÊM. a traves del uso de indicadores fluorescentes, determinamos que este compuesto desestabiliza el potencial electrogenicomitocondrial y genera alcalinizacion de los acidocalcisomas en estos parasitos. adicionalmente y a traves de estudiosde GC/MS, determinamos que el jC25 interfiere con la biosintesis de esteroles de estos parasitos, afectando la actividadde la enzima escualeno epoxidasa. Estos eventos explicarian en parte, el efecto leishmanicida observado. Finalmente,el jC25 genero un potente efecto sobre la viabilidad de amastigotes intracelulares de L. braziliensis (iC50: 12,78ƒÊM), sin afec -tar la viabilidad de las celulas hospederas. Teniendo en cuenta que el amastigote intracelular es el estadio terapeuticamenteimportante de la Leishmaniasis, el efecto mencionado anteriormente resulta muy interesante y permite realizar estudiosmas avanzados con este compuesto, o algunos otros con estructuras similares