Navegando por Autor "Araújo, Julianna Siciliano de"

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Phenotypic screening of novel aromatic amidines against Trypanosoma cruzi.
(2016) Silva, Marianne Rocha Simões; Gama, Aline Nefertiti Silva da; Araújo, Julianna Siciliano de; Batista, Marcos Meuser; Silva, Patrícia Bernardino da; Bahia, Maria Terezinha; Barreto, Rubem Figueiredo Sadok Menna; Pavão., Beatriz Philot; Green, Julius; Farahay, Abdelbaset A.; Kumar, Arvind; Boykin, David Wilson; Soeiro, Maria de Nazaré Correia
The current treatment of Chagas disease (CD), based on nifurtimox and benznidazole (Bz), is unsatisfactory. In this context, we performed the phenotypic in vitro screening of novel mono- and diamidines and drug interaction assays with selected compounds. Ten novel amidines were tested for their activities against bloodstream trypomastigote (BT) and amastigote forms of Trypanosoma cruzi (Y and Tulahuen strains) and their toxicities for mammalian host cells (L929 cells and cardiac cells). Seven of 10 molecules were more active than Bz against BT, with the most active compound being the diamidine DB2267 (50% effective concentration [EC50] 0.23 M; selectivity index 417), which was 28-fold more active and about 3 times more selective than the standard drug. Five of the six monoamidines were also more active than Bz. The combination of DB2267 and DB2236 in fixed-ratio proportions showed an additive effect (sum of fractional inhibitory concentrations<4) on BT. Interestingly, when intracellular forms were exposed to DB2267, its activity was dependent on the parasite strain, being effective (EC50 0.87 0.05 M) against a discrete typing unit (DTU) II strain (strain Y) but not against a representative DTU VI strain (strain Tulahuen) even when different vehicles ( -cyclodextrin and dimethyl sulfoxide) were used. The intrinsic fluorescence of several diamidines allowed their uptake to be studied. Testing of the uptake of DB2236 (inactive) and DB2267 (active) by amastigotes of the Y strain showed that the two compounds were localized intracellularly in different compartments: DB2236 in the cytoplasm and DB2267 in the nucleus. Our present data encourage further studies regarding the activities of amidines and provide information which will help with the identification of novel agents for the treatment of CD.
Repurposing strategies for Chagas disease therapy : the effect of imatinib and derivatives against Trypanosoma cruzi.
(2019) Silva, Marianne Rocha Simões; Araújo, Julianna Siciliano de; Peres, Raiza Brandão; Silva, Patrícia Bernardino da; Batista, Marcos Meuser; Azevedo, Liviane Dias de; Bastos, Mônica Macedo; Bahia, Maria Terezinha; Boechat, Núbia; Soeiro, Maria de Nazaré Correia
Chagas disease (CD) is a neglected parasitic condition endemic in the Americas caused by Trypanosoma cruzi. Patients present an acute phase that may or not be symptomatic, followed by lifelong chronic stage, mostly indeterminate, or with cardiac and/or digestive progressive lesions. Benznidazole (BZ) and nifurtimox are the only drugs approved for treatment but not effective in the late chronic phase and many strains of the parasite are naturally resistant. New alternative therapy is required to address this serious public health issue. Repositioning and combination represent faster, and cheaper trial strategies encouraged for neglected diseases. The effect of imatinib (IMB), a tyrosine kinase inhibitor designed for use in neoplasias, was assessed in vitro on T. cruzi and mammalian host cells. In comparison with BZ, IMB was moderately active against different strains and forms of the parasite. The combination IMB + BZ in fixed-ratio proportions was additive. Novel 14 derivatives of IMB were screened and a 3,2-difluoro-2-phenylacetamide (3e) was as potent as BZ on T. cruzi but had low selectivity index. The results demonstrate the importance of phenotypic assays, encourage the improvement of IMB derivatives to reach selectivity and testify to the use of repurposing and combination in drug screening for CD.