2. Academic Validation
  3. Synthesis and structure-activity relationship study of a new series of antiparasitic aryloxyl thiosemicarbazones inhibiting Trypanosoma cruzi cruzain

Synthesis and structure-activity relationship study of a new series of antiparasitic aryloxyl thiosemicarbazones inhibiting Trypanosoma cruzi cruzain

  • Eur J Med Chem. 2015 Aug 28:101:818-35. doi: 10.1016/j.ejmech.2015.06.048.
José Wanderlan Pontes Espíndola 1,  Marcos Veríssimo de Oliveira Cardoso 1,  Gevanio Bezerra de Oliveira Filho 1,  Dayane Albuquerque Oliveira E Silva 1,  Diogo Rodrigo Magalhaes Moreira 2,  Tanira Matutino Bastos 2,  Carlos Alberto de Simone 3,  Milena Botelho Pereira Soares 4,  Filipe Silva Villela 5,  Rafaela Salgado Ferreira 5,  Maria Carolina Accioly Brelaz de Castro 6,  Valéria Rego Alves Pereira 6,  Silvane Maria Fonseca Murta 7,  Policarpo Ademar Sales Junior 7,  Alvaro José Romanha 7,  Ana Cristina Lima Leite 8
Affiliations

Affiliations

  • 1 Departamento de Ciências Farmacêuticas, Centro de Ciências da Saúde, Universidade Federal de Pernambuco, 50740-520, Recife, PE, Brazil.
  • 2 Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz, 40296-750, Salvador, BA, Brazil.
  • 3 Departamento de Física e Informática, Instituto de Física, Universidade de São Paulo, 13560-970, São Carlos, SP, Brazil.
  • 4 Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz, 40296-750, Salvador, BA, Brazil; Centro de Biotecnologia e Terapia Celular, Hospital São Rafael, 41253-190, Salvador, BA, Brazil.
  • 5 Departamento de Bioquímica e Imunologia, Universidade Federal de Minas Gerais, 31270-901, Belo Horizonte, MG, Brazil.
  • 6 Centro de Pesquisas Aggeu Magalhães, Fundação Oswaldo Cruz, 50670-420, Recife, PE, Brazil.
  • 7 Laboratório de Parasitologia Celular e Molecular, Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz, 30.190-002, Belo Horizonte, MG, Brazil.
  • 8 Departamento de Ciências Farmacêuticas, Centro de Ciências da Saúde, Universidade Federal de Pernambuco, 50740-520, Recife, PE, Brazil. Electronic address: acllb2003@yahoo.com.
PMID: 26231082 DOI: 10.1016/j.ejmech.2015.06.048
Abstract

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 structure-activity 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.

Keywords

Chagas disease; Conformationally constrained analogs; Cruzain; Necrosis; Thiosemicarbazone; Trypanosoma cruzi.

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