Phenotypic screening of novel aromatic amidines against Trypanosoma cruzi.
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2016
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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.
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SILVA, M. R. S. et al. Phenotypic screening of novel aromatic amidines against Trypanosoma cruzi. Antimicrobial Agents and Chemotherapy, v. 60, p. 4701-4707, 2016. Disponível em: <http://aac.asm.org/content/60/8/4701.long>. Acesso em: 15 set. 2017.