title: Synthesis and structure-activity relationship study of a new series of antiparasitic aryloxyl thiosemicarbazones inhibiting Trypanosoma cruzi cruzain.
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.
authors.affiliation: Departamento de Ciências Farmacêuticas, Centro de Ciências da Saúde, Universidade Federal de Pernambuco, 50740-520, Recife, PE, Brazil.
authors.forename: José Wanderlan Pontes
authors.initials: JW
authors.lastname: Espíndola
authors.affiliation: Departamento de Ciências Farmacêuticas, Centro de Ciências da Saúde, Universidade Federal de Pernambuco, 50740-520, Recife, PE, Brazil.
authors.forename: Marcos Veríssimo de Oliveira
authors.initials: MV
authors.lastname: Cardoso
authors.affiliation: Departamento de Ciências Farmacêuticas, Centro de Ciências da Saúde, Universidade Federal de Pernambuco, 50740-520, Recife, PE, Brazil.
authors.forename: Gevanio Bezerra de Oliveira
authors.initials: GB
authors.lastname: Filho
authors.affiliation: Departamento de Ciências Farmacêuticas, Centro de Ciências da Saúde, Universidade Federal de Pernambuco, 50740-520, Recife, PE, Brazil.
authors.forename: Dayane Albuquerque
authors.initials: DA
authors.lastname: Oliveira E Silva
authors.affiliation: Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz, 40296-750, Salvador, BA, Brazil.
authors.forename: Diogo Rodrigo Magalhaes
authors.initials: DR
authors.lastname: Moreira
authors.affiliation: Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz, 40296-750, Salvador, BA, Brazil.
authors.forename: Tanira Matutino
authors.initials: TM
authors.lastname: Bastos
authors.affiliation: Departamento de Física e Informática, Instituto de Física, Universidade de São Paulo, 13560-970, São Carlos, SP, Brazil.
authors.forename: Carlos Alberto de
authors.initials: CA
authors.lastname: Simone
authors.affiliation: 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.
authors.forename: Milena Botelho Pereira
authors.initials: MB
authors.lastname: Soares
authors.affiliation: Departamento de Bioquímica e Imunologia, Universidade Federal de Minas Gerais, 31270-901, Belo Horizonte, MG, Brazil.
authors.forename: Filipe Silva
authors.initials: FS
authors.lastname: Villela
authors.affiliation: Departamento de Bioquímica e Imunologia, Universidade Federal de Minas Gerais, 31270-901, Belo Horizonte, MG, Brazil.
authors.forename: Rafaela Salgado
authors.initials: RS
authors.lastname: Ferreira
authors.affiliation: Centro de Pesquisas Aggeu Magalhães, Fundação Oswaldo Cruz, 50670-420, Recife, PE, Brazil.
authors.forename: Maria Carolina Accioly Brelaz de
authors.initials: MC
authors.lastname: Castro
authors.affiliation: Centro de Pesquisas Aggeu Magalhães, Fundação Oswaldo Cruz, 50670-420, Recife, PE, Brazil.
authors.forename: Valéria Rego Alves
authors.initials: VR
authors.lastname: Pereira
authors.affiliation: Laboratório de Parasitologia Celular e Molecular, Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz, 30.190-002, Belo Horizonte, MG, Brazil.
authors.forename: Silvane Maria Fonseca
authors.initials: SM
authors.lastname: Murta
authors.affiliation: Laboratório de Parasitologia Celular e Molecular, Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz, 30.190-002, Belo Horizonte, MG, Brazil.
authors.forename: Policarpo Ademar
authors.initials: PA
authors.lastname: Sales Junior
authors.affiliation: Laboratório de Parasitologia Celular e Molecular, Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz, 30.190-002, Belo Horizonte, MG, Brazil.
authors.forename: Alvaro José
authors.initials: AJ
authors.lastname: Romanha
authors.affiliation: Departamento de Ciências Farmacêuticas, Centro de Ciências da Saúde, Universidade Federal de Pernambuco, 50740-520, Recife, PE, Brazil. Electronic address: acllb2003@yahoo.com.
authors.forename: Ana Cristina Lima
authors.initials: AC
authors.lastname: Leite
mesh_terms: D018360:Crystallography, X-Ray; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013882:Thiosemicarbazones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000201:enzymology
chemical_list: D004791:Enzyme Inhibitors; D015800:Protozoan Proteins; D013882:Thiosemicarbazones; D014344:Trypanocidal Agents; D003546:Cysteine Endopeptidases; C074032:cruzain, Trypanosoma cruzi
keywords: Chagas disease; Conformationally constrained analogs; Cruzain; Necrosis; Thiosemicarbazone; Trypanosoma cruzi