Conformational restriction of aryl thiosemicarbazones produces potent and selective anti-Trypanosoma cruzi compounds which induce apoptotic parasite death.
Conformational restriction of aryl thiosemicarbazones produces potent and selective anti-Trypanosoma cruzi compounds which induce apoptotic parasite death.
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DOI：
10.1016/j.ejmech.2014.02.001
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发表时间：
2014-03
影响因子：
6.7
通讯作者：
Diogo Rodrigo Magalhaes Moreira;A. P. D. de Oliveira;Paulo André Teixeira de Moraes Gomes;C. A. de Simone;F. S. Villela;R. S. Ferreira;A. C. da Silva;T. D. dos Santos;Maria Carolina Accioly Brelaz de Castro;V. Pereira;A. Leite
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文献类型：
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作者：
Diogo Rodrigo Magalhaes Moreira;A. P. D. de Oliveira;Paulo André Teixeira de Moraes Gomes;C. A. de Simone;F. S. Villela;R. S. Ferreira;A. C. da Silva;T. D. dos Santos;Maria Carolina Accioly Brelaz de Castro;V. Pereira;A. Leite
Chagas disease, caused by Trypanosoma cruzi, is a life-threatening infection leading to approximately 12,000 deaths per year.T. cruziis susceptible to thiosemicarbazones, making this class of compounds appealing for drug development. Previously, the homologation of aryl thiosemicarbazones resulted in an increase in anti-T. cruziactivity in comparison to aryl thiosemicarbazones without a spacer group. Here, we report the structural planning, synthesis and anti-T. cruzievaluation of new aryl thiosemicarbazones (9a–x), designed as more conformationally restricted compounds. By varying substituents attached to the phenyl ring, substituents were observed to retain, enhance or greatly increase the anti-T. cruziactivity, in comparison to the nonsubstituted derivative. In most cases, hydrophobic and bulky substituents, such as bromo, biphenyl and phenoxyl groups, greatly increased antiparasitic activity. Specifically, thiosemicarbazones were identified that inhibit the epimastigote proliferation and were toxic for trypomastigotes without affecting mouse splenocytes viability. The most potent anti-T. cruzithiosemicarbazones were evaluated against cruzain. However, inhibition of this enzyme was not observed, suggesting that the compounds work through another mechanism. In addition, examination ofT. cruzicell death showed that these thiosemicarbazones induce apoptosis. In conclusion, the structural design executed within the series of aryl thiosemicarbazones (9a–x) led to the identification of new potent anti-T. cruziagents, such as compounds (9h) and (9r), which greatly inhibited epimastigote proliferation, and demonstrated a toxicity for trypomastigotes, but not for splenocytes. Mechanistically, these compounds do not inhibit the cruzain, but induceT. cruzicell death by an apoptotic process.
