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Chiara Pizzo,
Cecilia Saiz,
Alan Talevi,
Luciana Gavernet,
Pablo Palestro,
Carolina Bellera,
Luis Bruno Blanch,
Diego Benítez,
Juan J Cazzulo, Agustina Chidichimo,
Peter Wipf,
S Graciela Mahler
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ABSTRACT: A series of 18 novel 2-hydrazolyl-4-thiazolidinones-5-carboxylic acids, amides and 5,6-α,β-unsaturated esters were synthesized, and their in vitro activity on cruzipain and T. cruzi epimastigotes was determined. Some agents show activity at 37 μm concentration in the enzyme assay. Computational tools and docking were used to correlate the biological response with the physicochemical parameters of the compounds and their cruzipain inhibitory effects.
Chemical Biology & Drug Design 03/2011; 77(3):166-72. · 2.28 Impact Factor
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Chiara Pizzo,
Cecilia Saiz,
Alan Talevi,
Luciana Gavernet,
Pablo Palestro,
Carolina Bellera,
Luis Bruno Blanch,
Diego Benítez,
Juan J. Cazzulo, Agustina Chidichimo,
Peter Wipf,
S. Graciela Mahler
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[hide abstract]
ABSTRACT: A series of 18 novel 2-hydrazolyl-4-thiazolidinones-5-carboxylic acids, amides and 5,6-,β-unsaturated esters were synthesized, and their in vitro activity on cruzipain and T. cruzi epimastigotes was determined. Some agents show activity at 37 μm concentration in the enzyme assay. Computational tools and docking were used to correlate the biological response with the physicochemical parameters of the compounds and their cruzipain inhibitory effects.
Chemical Biology & Drug Design 01/2011; 77(3):166 - 172. · 2.28 Impact Factor
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ABSTRACT: Exploring the influence of different substitution patterns of 2H-benzimidazole 1,3-dioxide derivatives (BzNO) we prepared fifteen new derivatives. Initially the BzNO were tested against Trypanosoma cruzi Tulahuen 2 strain epimastigote form rendering very potent anti-T. cruzi agents. Moreover, the BzNO were able to inhibit the growth of virulent and resistant to Benznidazole strains (CL Brener clone, Colombiana, and Y strains) and to Leishmania braziliensis. Interestingly, BzNO exhibited very high selectivity index and particularly the spiro-BzNO 13 provokes an important diminution of amastigotes in Vero cells. Besides, it was found a diminution of acetate and glycine as excreted metabolites but without increase of parasite glucose uptake indicating that the glycosome is probably not involucrate in the 2H-benzimidazole 1,3-dioxides mechanism of action.
European journal of medicinal chemistry 07/2009; 44(11):4426-33. · 3.27 Impact Factor
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ABSTRACT: A series of over a hundred furoxans, alkylnitrates and related compounds were studied as growth inhibitors of the two major kinetoplastids of Latin America, Trypanosoma cruziand Leishmania spp., in in vitro assays. The most active compounds showed 50% inhibitory doses of the same order of that of Nifurtimox and Miltefosine, reference drugs used to treat Chagas Disease and Leishmaniasis respectively. Among the studied compounds derivative 4, presenting excellent inhibitory activity against the tryposmastigote and amastigote forms of T. cruzi, has emerged as a lead compound. Mechanism of action seems to involve mitochondrial dehydrogenases as a distinct effect with respect to Nifurtimox. Excreted metabolites, studied by NMR, showed a significant decrease in succinate, confirming the observed effect on the mitochrondrial dehydrogenases.
Bioorganic & medicinal chemistry 10/2008; 16(17):7900-7. · 2.82 Impact Factor
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ABSTRACT: Hybrid compounds containing hydrazones and benzofuroxan pharmacophores were designed as potential Trypanosoma cruzi-enzyme inhibitors. The majority of the designed compounds was successfully synthesized and biologically evaluated displaying remarkable in vitro activity against different strains of T. cruzi. Unspecific cytotoxicity was evaluated using mouse macrophages, displaying isothiosemicarbazone 10 and thiosemicarbazone 12 selectivity indexes (macrophage/parasite) of 21 and 27, respectively. In addition, the mode of anti-trypanosomal action of the derivatives was investigated. Some of these derivatives were moderate inhibitors of cysteinyl active site enzymes of T. cruzi, cruzipain and trypanothione reductase. ESR experiments using T. cruzi microsomal fraction suggest that the main mechanism of action of the trypanocidal effects is the production of oxidative stress into the parasite.
Bioorganic & medicinal chemistry 06/2008; 16(14):6995-7004. · 2.82 Impact Factor
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Williams Porcal,
Paola Hernández,
Mariana Boiani,
Gabriela Aguirre,
Lucía Boiani, Agustina Chidichimo,
Juan J Cazzulo,
Nuria E Campillo,
Juan A Paez,
Ana Castro,
R Luise Krauth-Siegel,
Carolina Davies,
Miguel Angel Basombrío,
Mercedes González,
Hugo Cerecetto
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ABSTRACT: New benzofuroxans were developed and studied as antiproliferative Trypanosoma cruzi agents. Compounds displayed remarkable in vitro activities against different strains, Tulahuen 2, CL Brener and Y. Its unspecific cytotoxicity was evaluated using human macrophages being not toxic at a concentration at least 8 times, and until 250 times, that of its T. cruzi IC50. Some biochemical pathways were studied, namely parasite respiration, cysteinyl active site enzymes and reaction with glutathione, as target for the mechanism of action. Not only T. cruzi respiration but also Cruzipain or trypanothione reductase were not affected, however the most active derivatives, the vinylsulfinyl- and vinylsulfonyl-containing benzofuroxans, react with glutathione in a redox pathway. Furthermore, the compounds showed good in vivo activities when they were studied in an acute murine model of Chagas' disease. The compounds were able to reduce the parasite loads of animals with fully established T. cruzi infections.
Journal of Medicinal Chemistry 12/2007; 50(24):6004-15. · 5.25 Impact Factor
