Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 4 de 4
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Vet Parasitol ; 177(1-2): 157-61, 2011 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-21176865

RESUMO

Previous studies from our group have demonstrated the high susceptibility of Toxoplasma gondii tachyzoites to the sterol analogues 22,26-azasterol and 24,25-(R,S)-epiminolanosterol. In this work we present data on testing in vitro three novel azasterols as potential agents for the treatment of toxoplasmosis. The three compounds inhibited parasite growth at micromolar concentrations, in a dose-dependent manner. Electron microscopy analysis of intracellular tachyzoites after treatment with the most effective compound showed drastic mitochondrion swelling associated with the appearance of an electron-lucent matrix and disrupted cristae. Parasite lysis also took place. The appearance of electron dense cytoplasmic structures similar to amylopectin granules distributed throughout the parasite suggests that azasterols might be inducing differentiation of those tachyzoites which were not lysed to the bradyzoite stage.


Assuntos
Coccidiostáticos/farmacologia , Esteróis/farmacologia , Toxoplasma/efeitos dos fármacos , Animais , Coccidiostáticos/química , Estrutura Molecular , Esteróis/química
2.
Biochem Biophys Res Commun ; 363(2): 310-6, 2007 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-17870055

RESUMO

The effects of sterol biosynthesis inhibitors on growth and fine structure of Giardia lamblia P1 strain cultures were analyzed. Azasterols demonstrated high efficacy in killing cells. The IC(50) values for 22,26-azasterol and 24(R,S),25-epiminolanosterol were 7muM and 170nM, respectively. Morphological analysis showed that azasterols induced changes in G. lamblia ultrastructure. The most significant alterations were: (a) considerable increase of the size of the peripheral vesicles, which are part of the parasite endosomal-lysosomal system; (b) appearance of autophagosomal structures; and (c) induction of differentiation, followed by an abnormal enlargement of encystation secretory vesicles. We propose that azasterols are effective chemotherapeutic drugs against Giardia lamblia in vitro and may have another target in cells besides sterol biosynthesis.


Assuntos
Antiprotozoários/administração & dosagem , Azasteroides/administração & dosagem , Giardia lamblia/efeitos dos fármacos , Giardia lamblia/crescimento & desenvolvimento , Trofozoítos/efeitos dos fármacos , Trofozoítos/crescimento & desenvolvimento , Animais , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Giardia lamblia/citologia , Dose Letal Mediana , Trofozoítos/citologia
3.
Microsc Microanal ; 11(6): 506-15, 2005 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17481329

RESUMO

Trypanosoma cruzi is the ethiological agent of Chagas disease. New compounds are being developed based on the biosynthesis and function of sterols, because T. cruzi has a requirement for specific endogenous sterols for growth and survival. Sterol biosynthesis inhibitors (SBIs) are drugs commonly used against fungal diseases. These drugs act by depleting essential and specific membrane components and/or inducing the accumulation of toxic intermediary or lateral products of the biosynthetic pathway. In this work we present the effects of WSP488, WSP501, and WSP561, specific inhibitors of Delta24(25)-sterol methyl transferase, on the ultrastructure of T. cruzi epimastigotes. All three drugs inhibited parasite multiplication at low concentrations, with IC50 values of 0.48, 0.44, and 0.48 muM, respectively, and induced marked morphological changes including (a) blockage of cell division; (b) swelling of the mitochondrion, with several projections and depressions; (c) swelling of the perinuclear space; (d) presence of autophagosomes and myelin-like figures; (e) enlargement of the flagellar pocket and of a cytoplasmic vacuole located in close association with the flagellar pocket; (f) detachment of the membrane of the cell body; and (g) formation of a vesicle at the surface of the parasite between the flagellar pocket and the cytostome. Our results show that these drugs are potent in vitro inhibitors of growth of T. cruzi.


Assuntos
Inibidores Enzimáticos/farmacologia , Metiltransferases/antagonistas & inibidores , Trypanosoma cruzi/crescimento & desenvolvimento , Animais , Autofagia , Membrana Celular/efeitos dos fármacos , Membrana Celular/ultraestrutura , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Trypanosoma cruzi/ultraestrutura , Vacúolos/efeitos dos fármacos , Vacúolos/ultraestrutura
4.
J Med Chem ; 46(22): 4714-27, 2003 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-14561091

RESUMO

This paper describes the synthesis of some novel azasterols based on (20R,22xi)-5alpha-pregnan-20-(piperidin-2-yl)-3beta,20-diol. These compounds are potential inhibitors of the enzyme sterol 24-methyltransferase (24-SMT), which is a vital enzyme in the biosynthesis of ergosterol and related 24-alkyl sterols. Structure-activity studies were undertaken to understand the important features for activity against the enzyme, with the aim of increasing activity and selectivity. The compounds were evaluated for inhibition of recombinant Leishmania major 24-SMT and the effect of compounds on sterol composition and parasite proliferation. Essentially, compounds which showed good activity against the recombinant enzyme had a significant effect on the sterol composition and growth of parasites. The activity of compounds was found to be related to the basicity and stereochemical location of the nitrogen. Also, presence of an unprotected 3beta-OH seemed to be important for activity. However, some azasterols which were not good inhibitors of 24-SMT also showed antiproliferative activity, suggesting that there may be other modes of actions of these compounds.


Assuntos
Compostos Aza/síntese química , Inibidores Enzimáticos/síntese química , Leishmania/efeitos dos fármacos , Metiltransferases/antagonistas & inibidores , Pregnanodiol/síntese química , Esteróis/síntese química , Tripanossomicidas/síntese química , Trypanosoma/efeitos dos fármacos , Animais , Compostos Aza/química , Compostos Aza/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Leishmania/enzimologia , Leishmania/ultraestrutura , Metiltransferases/química , Pregnanodiol/análogos & derivados , Pregnanodiol/química , Pregnanodiol/farmacologia , Proteínas Recombinantes/química , Especificidade da Espécie , Esteróis/química , Esteróis/farmacologia , Relação Estrutura-Atividade , Tripanossomicidas/química , Tripanossomicidas/farmacologia , Trypanosoma/enzimologia , Trypanosoma/ultraestrutura
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...