title: Conformational restriction of aryl thiosemicarbazones produces potent and selective anti-Trypanosoma cruzi compounds which induce apoptotic parasite death.
abstract: Chagas disease, caused by Trypanosoma cruzi, is a life-threatening infection leading to approximately 12,000 deaths per year. T. cruzi is 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. cruzi activity in comparison to aryl thiosemicarbazones without a spacer group. Here, we report the structural planning, synthesis and anti-T. cruzi evaluation 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. cruzi activity, 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. cruzi thiosemicarbazones were evaluated against cruzain. However, inhibition of this enzyme was not observed, suggesting that the compounds work through another mechanism. In addition, examination of T. cruzi cell 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. cruzi agents, 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 induce T. cruzi cell death by an apoptotic process.
authors.affiliation: Fundação Oswaldo Cruz, Centro de Pesquisas Gonçalo Moniz, CEP 40296-710 Salvador, BA, Brazil. Electronic address: diogollucio@gmail.com.
authors.forename: Diogo Rodrigo
authors.initials: DR
authors.lastname: Magalhaes Moreira
authors.affiliation: Universidade Federal de Pernambuco, Departamento de Ciências Farmacêuticas, CEP 50740-520 Recife, PE, Brazil.
authors.forename: Ana Daura Travassos
authors.initials: AD
authors.lastname: de Oliveira
authors.affiliation: Universidade Federal de Pernambuco, Departamento de Ciências Farmacêuticas, CEP 50740-520 Recife, PE, Brazil.
authors.forename: Paulo André
authors.initials: PA
authors.lastname: Teixeira de Moraes Gomes
authors.affiliation: Universidade de São Paulo, Instituto de Física de São Carlos, CEP 13560-970 São Carlos, SP, Brazil.
authors.forename: Carlos Alberto
authors.initials: CA
authors.lastname: de Simone
authors.affiliation: Universidade Federal de Minas Gerais, Departamento de Bioquímica e Imunologia, CEP 31270-901 Belo Horizonte, MG, Brazil.
authors.forename: Filipe Silva
authors.initials: FS
authors.lastname: Villela
authors.affiliation: Universidade Federal de Minas Gerais, Departamento de Bioquímica e Imunologia, CEP 31270-901 Belo Horizonte, MG, Brazil.
authors.forename: Rafaela Salgado
authors.initials: RS
authors.lastname: Ferreira
authors.affiliation: Fundação Oswaldo Cruz, Centro de Pesquisas Aggeu Magalhães, CEP 50670-420 Recife, PE, Brazil.
authors.forename: Aline Caroline
authors.initials: AC
authors.lastname: da Silva
authors.affiliation: Fundação Oswaldo Cruz, Centro de Pesquisas Aggeu Magalhães, CEP 50670-420 Recife, PE, Brazil.
authors.forename: Thiago André Ramos
authors.initials: TA
authors.lastname: dos Santos
authors.affiliation: Fundação Oswaldo Cruz, Centro de Pesquisas Aggeu Magalhães, CEP 50670-420 Recife, PE, Brazil.
authors.forename: Maria Carolina Accioly
authors.initials: MC
authors.lastname: Brelaz de Castro
authors.affiliation: Fundação Oswaldo Cruz, Centro de Pesquisas Aggeu Magalhães, CEP 50670-420 Recife, PE, Brazil.
authors.forename: Valéria Rego Alves
authors.initials: VR
authors.lastname: Pereira
authors.affiliation: Universidade Federal de Pernambuco, Departamento de Ciências Farmacêuticas, CEP 50740-520 Recife, PE, Brazil. Electronic address: ana.leite@pq.cnpq.br.
authors.forename: Ana Cristina Lima
authors.initials: AC
authors.lastname: Leite
mesh_terms: D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D014355:Chagas Disease / Q000188:drug therapy; D057056:Cysteine Proteases / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008968:Molecular Conformation; D013154:Spleen / Q000166:cytology / Q000469:parasitology; D013329:Structure-Activity Relationship; D013882:Thiosemicarbazones / Q000737:chemistry* / Q000494:pharmacology*; D014344:Trypanocidal Agents / Q000737:chemistry* / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology
chemical_list: D015853:Cysteine Proteinase Inhibitors; D013882:Thiosemicarbazones; D014344:Trypanocidal Agents; D057056:Cysteine Proteases
keywords: Apoptosis; Chagas disease; Conformational restriction; Hydrazones; Thiosemicarbazones; Trypanosoma cruzi