title: Desing and synthesis of potent anti-Trypanosoma cruzi agents new thiazoles derivatives which induce apoptotic parasite death.
abstract: Chagas disease, caused by the kinetoplastid protozoan parasite Trypanosoma cruzi, remains a relevant cause of illness and premature death and it is estimated that 6 million to 7 million people are infected worldwide. Although chemotherapy options are limited presenting serious problems, such as low efficacy and high toxicity. T. cruzi is susceptible to thiazoles, making this class of compounds appealing for drug development. Previously, thiazoles resulted in an increase in anti-T. cruzi activity in comparison to thiosemicarbazones. Here, we report the structural planning, synthesis and anti-T. cruzi evaluation of new thiazoles derivatives (3a-m and 4a-m), designed from molecular hybridization associated with non-classical bioisosterism. By varying substituents attached to the phenyl and thiazole rings, substituents were observed to retain, enhance or greatly increase their anti-T. cruzi activity, in comparison to the corresponding thiosemicarbazones. In most cases, electron-withdrawing substituents, such as bromine, 3,4-dichloro and nitro groups, greatly increased antiparasitic activity. Specifically, new thiazoles were identified that inhibit the epimastigote proliferation and were toxic for trypomastigotes without affecting macrophages viability. These compounds were also 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 molecules induce apoptosis. In conclusion, except for compounds 3h and 3k, all thiazoles derivatives evaluated exhibited higher cytotoxic activity against the trypomastigote forms than the reference medicament benznidazole, without affecting macrophages viability. Compounds 4d and 4k were highlights, CC50 = 1.2 e 1.6 μM, respectively. Mechanistically, these compounds do not inhibit the cruzain, but induce T. cruzi cell death by an apoptotic process, being considered a good starting point for the development of new anti-Chagas drug candidates.
authors.affiliation: Departamento de Ciências Farmacêuticas, Centro de Ciências da Saúde, Universidade Federal de Pernambuco, 50740-520, Recife, PE, Brazil; Departamento de Bioquímica e Imunologia, Universidade Federal de Minas Gerais, 31270-901, Belo Horizonte, MG, Brazil.
authors.forename: Elany Barbosa
authors.initials: EB
authors.lastname: da Silva
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: Departamento de Ciências Farmacêuticas, Centro de Ciências da Saúde, Universidade Federal de Pernambuco, 50740-520, Recife, PE, Brazil.
authors.forename: Arsênio Rodrigues
authors.initials: AR
authors.lastname: Oliveira
authors.affiliation: Departamento de Ciências Farmacêuticas, Centro de Ciências da Saúde, Universidade Federal de Pernambuco, 50740-520, Recife, PE, Brazil.
authors.forename: Carlos Henrique
authors.initials: CH
authors.lastname: da Silva Mendes
authors.affiliation: Centro de Pesquisas Aggeu Magalhães, Fundação Oswaldo Cruz, 50670-420, Recife, PE, Brazil.
authors.forename: Thiago André Ramos
authors.initials: TA
authors.lastname: Dos Santos
authors.affiliation: Centro de Pesquisas Aggeu Magalhães, Fundação Oswaldo Cruz, 50670-420, Recife, PE, Brazil.
authors.forename: Aline Caroline
authors.initials: AC
authors.lastname: da Silva
authors.affiliation: Centro de Pesquisas Aggeu Magalhães, Fundação Oswaldo Cruz, 50670-420, Recife, PE, Brazil; Laboratório de Parasitologia, Centro Acadêmico de Vitória, Universidade Federal de Pernambuco, 55608-680, Vitória de Santo Antão, PE, Brazil.
authors.forename: Maria Carolina Acioly
authors.initials: MC
authors.lastname: de Castro
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 Gonçalo Moniz, Fundação Oswaldo Cruz, 40296-750, Salvador, BA, Brazil.
authors.forename: Diogo Rodrigo Magalhães
authors.initials: DR
authors.lastname: Moreira
authors.affiliation: Colegiado de Nutrição, Campus Petrolina, Universidade de Pernambuco, 56328-903, Petrolina, PE, Brazil.
authors.forename: Marcos Veríssimo de Oliveira
authors.initials: MV
authors.lastname: Cardoso
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: Centro de Pesquisas Aggeu Magalhães, Fundação Oswaldo Cruz, 50670-420, Recife, PE, Brazil.
authors.forename: Valéria Rêgo Alves
authors.initials: VR
authors.lastname: Pereira
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.br.
authors.forename: Ana Cristina Lima
authors.initials: AC
authors.lastname: Leite
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D014355:Chagas Disease / Q000188:drug therapy; D003546:Cysteine Endopeptidases / Q000187:drug effects; D015195:Drug Design; D021261:Parasitic Sensitivity Tests; D015800:Protozoan Proteins / Q000187:drug effects; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry / Q000493:pharmacokinetics*; D014344:Trypanocidal Agents / Q000737:chemistry* / Q000494:pharmacology; D014349:Trypanosoma cruzi / Q000166:cytology / Q000187:drug effects*
chemical_list: D015800:Protozoan Proteins; D013844:Thiazoles; D014344:Trypanocidal Agents; D003546:Cysteine Endopeptidases; C074032:cruzain, Trypanosoma cruzi
keywords: Apoptosis; Chagas disease; Nonclassical bioisosterism; Pyridine derivatives; Thiazoles; Trypanosoma cruzi