Article
Synthesis and structure-activity relationship study of a new series of antiparasitic aryloxyl thiosemicarbazones inhibiting Trypanosoma cruzi cruzain.
Registro en:
ESPINDOLA, J. W. P. et al. Synthesis and structure-activity relationship study of a new series of antiparasitic aryloxyl thiosemicarbazones inhibiting Trypanosoma cruzi cruzain. European Journal of Medicinal Chemistry, v. 101, p. 818-835, 2015.
1768-3254
dx.doi.org/10.1016/j.ejmech.2015.06.048
Autor
Espíndola, José Wanderlan Pontes
Cardoso, Marcos Veríssimo de Oliveira
Oliveira Filho, Gevanio Bezerra de
Silva, Dayane Albuquerque Oliveira e
Moreira, Diogo Rodrigo Magalhães
Bastos, Tanira Matutino
Simone, Carlos Alberto de
Soares, Milena Botelho Pereira
Villela, Filipe Silva
Ferreira, Rafaela Salgado
Castro, Maria Carolina Accioly Brelaz de
Pereira, Valeria Rego Alves
Murta, Silvane Maria Fonseca
Sales Junior, Policarpo Ademar
Romanha, Alvaro Jose
Leite, Ana Cristina Lima
Resumen
The discovery of new antiparasitic compounds against Trypanosoma cruzi, the etiological agent of Chagas
disease, is necessary. Novel aryloxy/aryl thiosemicarbazone-based conformationally constrained analogs
of thiosemicarbazones (1) and (2) were developed as potential inhibitors of the T. cruzi protease cruzain,
using a rigidification strategy of the iminic bond of (1) and (2). A structureeactivity relationship analysis
was performed in substituents attached in both aryl and aryloxy rings. This study indicated that apolar
substituents or halogen atom substitution at the aryl position improved cruzain inhibition and antiparasitic
activity in comparison to unsubstituted thiosemicarbazone. Two of these compounds displayed
potent inhibitory antiparasitic activity by inhibiting cruzain and consequently were able to reduce the
parasite burden in infected cells and cause parasite cell death through necrosis. In conclusion, we
demonstrated that conformational restriction is a valuable strategy in the development of antiparasitic
thiosemicarbazones.