title: Structural design, synthesis and pharmacological evaluation of 4-thiazolidinones against Trypanosoma cruzi.
abstract: Chagas disease is an infection caused by protozoan Trypanosoma cruzi, which affects approximately 8-10million people worldwide. Benznidazole is the only drug approved for treatment during the acute and asymptomatic chronic phases of Chagas disease; however, it has poor efficacy during the symptomatic chronic phase. Therefore, the development of new pharmaceuticals is needed. Here, we employed the bioisosterism to modify a potent antiparasitic and cruzain-inhibitor aryl thiosemicarbazone (4) into 4-thiazolidinones (7-21). Compounds (7-21) were prepared by using a straightforward synthesis and enabled good to excellent yields. As a chemical elucidation tool, X-ray diffraction of compound (10) revealed the geometry and conformation of this class compounds. The screening against cruzain showed that 4-thiazolidinones were less active than thiosemicarbazone (4). However, the antiparasitic activity in Y strain trypomastigotes and host cell cytotoxicity in J774 macrophages revealed that compounds (10 and 18-21) are stronger and more selective antiparasitic agents than thiosemicarbazone (4). Specifically, compounds (18-20), which carry a phenyl at position N3 of heterocyclic ring, were the most active ones, suggesting that this is a structural determinant for activity. In infected macrophages, compounds (18-20) reduced intracellular amastigotes, whereas Benznidazole did not. In T. cruzi-infected mice treated orally with 100mg/kg of compound (20), a decreased of parasitemia was observed. In conclusion, we demonstrated that the conversation of thiosemicarbazones into 4-thiazolidinones retains pharmacological property while enhances selectivity.
authors.affiliation: Departamento de Ciências Farmacêuticas, Centro de Ciências da Saúde, Universidade Federal de Pernambuco, 50740-520 Recife, PE, Brazil. Electronic address: gev_filho@hotmail.com.
authors.forename: Gevanio Bezerra
authors.initials: GB
authors.lastname: de Oliveira Filho
authors.affiliation: Departamento de Ciências Farmacêuticas, Centro de Ciências da Saúde, Universidade Federal de Pernambuco, 50740-520 Recife, PE, Brazil.
authors.forename: Marcos Veríssimo
authors.initials: MV
authors.lastname: de Oliveira Cardoso
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: Luiz Felipe Gomes Rebello
authors.initials: LF
authors.lastname: Ferreira
authors.affiliation: Departamento de Física e Informática, Instituto de Física, Universidade de São Paulo, CEP 13560-970, São Carlos, SP, Brazil.
authors.forename: Carlos Alberto
authors.initials: CA
authors.lastname: de Simone
authors.affiliation: Departamento de Bioquímica e Imunologia, Universidade Federal de Minas Gerais, CEP 31270-901, Belo Horizonte, MG, Brazil.
authors.forename: Rafaela Salgado
authors.initials: RS
authors.lastname: Ferreira
authors.affiliation: Departamento de Bioquímica e Imunologia, Universidade Federal de Minas Gerais, CEP 31270-901, Belo Horizonte, MG, Brazil.
authors.forename: Pollyanne Lacerda
authors.initials: PL
authors.lastname: Coelho
authors.affiliation: Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz, CEP 40296-710, Salvador, BA, Brazil.
authors.forename: Cássio Santana
authors.initials: CS
authors.lastname: Meira
authors.affiliation: Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz, CEP 40296-710, Salvador, BA, Brazil.
authors.forename: Diogo Rodrigo
authors.initials: DR
authors.lastname: Magalhaes Moreira
authors.affiliation: Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz, CEP 40296-710, Salvador, BA, Brazil; Centro de Biotecnologia e Terapia Celular, Hospital São Rafael, Salvador, BA, Brazil.
authors.forename: Milena Botelho Pereira
authors.initials: MB
authors.lastname: Soares
authors.affiliation: Departamento de Ciências Farmacêuticas, Centro de Ciências da Saúde, Universidade Federal de Pernambuco, 50740-520 Recife, PE, Brazil.
authors.forename: Ana Cristina
authors.initials: AC
authors.lastname: Lima Leite
mesh_terms: D000818:Animals; D003546:Cysteine Endopeptidases; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D006835:Hydrazones / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D009593:Nitroimidazoles / Q000627:therapeutic use; D018512:Parasitemia / Q000188:drug therapy; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D053778:Thiazolidines / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D013882:Thiosemicarbazones / Q000737:chemistry; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D014349:Trypanosoma cruzi / Q000187:drug effects*
chemical_list: C000610533:2-(1-(3,4-dichlorophenyl)ethylidenohydrazone)-3-phenyl-5-isopropylthiazolidin-4-one; D015853:Cysteine Proteinase Inhibitors; D006835:Hydrazones; D009593:Nitroimidazoles; D015800:Protozoan Proteins; D053778:Thiazolidines; D013882:Thiosemicarbazones; D014344:Trypanocidal Agents; D003546:Cysteine Endopeptidases; C074032:cruzain, Trypanosoma cruzi; C009999:benzonidazole
keywords: Bioisosterism; Chagas disease; Thiazolidinones; Thiosemicarbazones; Trypanosoma cruzi