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1.
Molecules ; 24(1)2018 Dec 31.
Artículo en Inglés | MEDLINE | ID: mdl-30602705

RESUMEN

The spectrum and efficacy of available antileishmanial drugs is limited. In the present work we evaluated in vitro the antiproliferative activity of 11 compounds based on tetradentate polyamines compounds against three Leishmania species (L. braziliensis, L. donovani and L. infantum) and the possible mechanism of action. We identified six compounds (3, 5, 6, 7, 8 and 10) effective against all three Leishmania spp both on extracellular and intracellular forms. These six most active leishmanicidal compounds also prevent the infection of host cells. Nevertheless, only compound 7 is targeted against the Leishmania SOD. Meanwhile, on the glucose metabolism the tested compounds have a species-specific effect on Leishmania spp.: L. braziliensis was affected mainly by 10 and 8, L. donovani by 7, and L. infantum by 5 and 3. Finally, the cellular ultrastructure was mainly damaged by 11 in the three Leishmania spp. studied. These identified antileishmania candidates constitute a good alternative treatment and will be further studied.


Asunto(s)
Antiprotozoarios/síntesis química , Leishmania/enzimología , Poliaminas/síntesis química , Superóxido Dismutasa/antagonistas & inhibidores , Animales , Antiprotozoarios/química , Antiprotozoarios/farmacología , Línea Celular , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Leishmania/efectos de los fármacos , Leishmania/patogenicidad , Macrófagos/citología , Macrófagos/efectos de los fármacos , Macrófagos/parasitología , Ratones , Microscopía Electrónica de Transmisión , Estructura Molecular , Pruebas de Sensibilidad Parasitaria , Poliaminas/química , Poliaminas/farmacología , Proteínas Protozoarias/antagonistas & inhibidores
2.
Exp Parasitol ; 170: 36-49, 2016 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-27480054

RESUMEN

In order to evaluate the in vitro leishmanicidal activity of N,N'-Squaramides derivatives, compounds that feature both hydrogen bond donor and acceptor groups and are capable of multiple interactions with complementary sites, against Leishmania infantum, Leishmania braziliensis and Leishmania donovani a series of 18compounds was prepared and assayed on extracellular and intracellular parasite forms. Infectivity and cytotoxicity tests were performed on J774.2 macrophage cells using meglumine antimoniate (Glucantime) as the reference drug. Changes in metabolite excretion by 1H-NMR and the ultrastructural alterations occurring in the parasites treated using transmission electron microscopy (TEM), was analyzed. Compounds 1, 7, 11, 14 and 17 were the more active and less toxic. Infection rates showed that the order of effectiveness was 17 > 11 > 14 > 7 for both L. infantum and L. braziliensis and in the same way, the compound 1 for L. donovani. All these compounds have altered the typical structure of the promastigotes, glycosomes and mitochondria. These severe modifications by the compounds are the ultimate reasons for the alterations observed in the excretion products. The Squaramide 17 (3-(butylamino)-4-((3-(dimetilamino)propyl)(methyl)amino)cyclobut-3-en-1,2-dione) was clearly the most efficient of all compounds. The data appear to confirm that the severe modifications generated in organelles such as glycosomes or mitochondria by the compounds are the ultimate reasons for the alterations observed in the excretion products of all species. The activity, stability, low cost of starting materials, and straightforward synthesis make amino squaramides appropriate molecules for the development of an affordable anti-leishmanial agent.


Asunto(s)
Leishmania braziliensis/efectos de los fármacos , Leishmania donovani/efectos de los fármacos , Leishmania infantum/efectos de los fármacos , Macrófagos/parasitología , Quinina/análogos & derivados , Animales , Línea Celular , Citometría de Flujo , Concentración 50 Inhibidora , Leishmania braziliensis/metabolismo , Leishmania braziliensis/ultraestructura , Leishmania donovani/metabolismo , Leishmania donovani/ultraestructura , Leishmania infantum/metabolismo , Leishmania infantum/ultraestructura , Macrófagos/efectos de los fármacos , Ratones , Microscopía Electrónica de Transmisión , Quinina/química , Quinina/farmacología , Quinina/toxicidad
3.
Int J Parasitol Drugs Drug Resist ; 5(3): 110-6, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26236582

RESUMEN

In order to identify new compounds to treat Chagas disease during the acute phase with higher activity and lower toxicity than the reference drug benznidazole (Bz), two hydroxyphthalazine derivative compounds were prepared and their trypanocidal effects against Trypanosoma cruzi were evaluated by light microscopy through the determination of IC50 values. Cytotoxicity was determined by flow cytometry assays against Vero cells. In vivo assays were performed in BALB/c mice, in which the parasitemia levels were quantified by fresh blood examination; the assignment of a cure was determined by reactivation of blood parasitemia levels after immunosuppression. The mechanism of action was elucidated at metabolic and ultra-structural levels, by (1)H NMR and TEM studies. Finally, as these compounds are potentially capable of causing oxidative damage in the parasites, the study was completed, by assessing their activity as potential iron superoxide dismutase (Fe-SOD) inhibitors. High-selectivity indices observed in vitro were the basis of promoting one of the tested compounds to in vivo assays. The tests on the murine model for the acute phase of Chagas disease showed better parasitemia inhibition values than those found for Bz. Compound 2 induced a remarkable decrease in the reactivation of parasitemia after immunosuppression. Compound 2 turned out to be a great inhibitor of Fe-SOD. The high antiparasitic activity and low toxicity together with the modest costs for the starting materials render this compound an appropriate molecule for the development of an affordable anti-Chagas agent.


Asunto(s)
Enfermedad de Chagas/parasitología , Nitroimidazoles/uso terapéutico , Parasitemia/tratamiento farmacológico , Superóxido Dismutasa/antagonistas & inhibidores , Trypanosoma cruzi/efectos de los fármacos , Animales , Enfermedad de Chagas/tratamiento farmacológico , Ciclofosfamida/toxicidad , Huésped Inmunocomprometido , Inmunosupresores/toxicidad , Ratones , Ratones Endogámicos BALB C , Estructura Molecular , Nitroimidazoles/química , Nitroimidazoles/farmacología , Tripanocidas/química , Tripanocidas/farmacología , Tripanocidas/uso terapéutico
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