| Author | Mello, Francisco do Vale Chaves e | |
| Author | Quaresma, Bruna Maria Castro Salomao | |
| Author | Pitombeira, Marcelly Cristina Resende | |
| Author | Brito, Monique Araújo de | |
| Author | Farias, Patrícia Pereira | |
| Author | Castro, Solange Lisboa de | |
| Author | Salomão, Kelly | |
| Author | Carvalho, Alcione Silva de | |
| Author | Paula, Jessica Isis Oliveira de | |
| Author | Nascimento, Suelen de Brito | |
| Author | Cupello, Mauricio Peixoto | |
| Author | Paes, Marcia Cristina | |
| Author | Boechat, Nubia | |
| Author | Felzenszwalb, Israel | |
| Access date | 2020-09-01T19:24:31Z | |
| Available date | 2020-09-01T19:24:31Z | |
| Document date | 2020 | |
| Citation | MELLO, Francisco do Vale Chaves e et al. Novel nitroimidazole derivatives evaluated for their trypanocidal, cytotoxic, and genotoxic activities. European Journal of Medicinal Chemistry, v. 186, p. 1-15, 2020. | pt_BR |
| ISSN | 0223-5234 | pt_BR |
| URI | https://www.arca.fiocruz.br/handle/icict/43143 | |
| Language | eng | pt_BR |
| Publisher | Science Direct | pt_BR |
| Rights | restricted access | |
| Subject in Portuguese | Doença de Chagas | pt_BR |
| Subject in Portuguese | Trypanosoma cruzi | pt_BR |
| Subject in Portuguese | Nitroimidazoles | pt_BR |
| Subject in Portuguese | Atividade genotóxica | pt_BR |
| Subject in Portuguese | Modelagem molecular | pt_BR |
| Title | Novel nitroimidazole derivatives evaluated for their trypanocidal, cytotoxic, and genotoxic activities | pt_BR |
| Type | Article | |
| DOI | 10.1016/j.ejmech.2019.111887 | |
| Abstract | The current treatment of Chagas disease is based on the use of two drugs, nifurtimox (Nfx) and benznidazole (Bnz), both of which present limited efficacy in the chronic stage of the disease and toxic side
effects. Thus, the discovery of novel compounds is urgently required. Herein, we report the successful
synthesis of 4-nitroimidazole analogs of Bnz via nucleophilic aromatic substitution or cycloaddition
reactions. The analogs were biologically evaluated, and compound 4 (4-cyclopropyl-1-(1-methyl-4-nitro1H-imidazole-5-yl)-1H-1,2,3-triazole) was identified as the most potent against both the trypomastigote
(IC50 ¼ 5.4 mM) and amastigote (IC50 ¼ 12.0 mM) forms of T. cruzi, showing activity in the same range as
Bnz (IC50 ¼ 8.8 and 8.7 mM, respectively). The cytotoxic and genotoxic activities of compounds 5, 4 and 11
were assessed. These three compounds were cytotoxic and genotoxic to RAW and HepG2 cells and
mutagenic to Salmonella enterica strains. However, 4 exhibited toxic effects only at concentrations higher
than those needed for trypanocidal activity. Molecular docking of 4 showed the importance of the size
and p-p interactions between the nitroimidazole and the cofactor (flavin mononucleotide) of T.cruzinitroreductase (TcNTR). Moreover, the residues His503 and Tyr545 are relevant for binding to TcNTR. Our
design strategy was capable of generating novel and active Bnz analogs. | pt_BR |
| Affilliation | Universidade do Estado do Rio de Janeiro. Instituto de Biologia Roberto Alcantara Gomes. Departamento de Biofísica e Biometria. Laboratorio de Mutagenese Ambiental. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Universidade Federal do Rio de Janeiro. Instituto de Ciencias Biomédicas. Programa de Pos-Graduacao Farmacologia e Quimica Medicinal. Rio de Janeiro, RJ, Brasil / Fundação Oswaldo Cruz. Farmanguinhos. LASFAR, Instituto de Tecnologia em Farmacos. Laboratorio de Sintese de Fármacos. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Universidade Federal do Rio de Janeiro. Instituto de Ciencias Biomédicas. Programa de Pos-Graduacao Farmacologia e Quimica Medicinal. Rio de Janeiro, RJ, Brasil / Fundação Oswaldo Cruz. Farmanguinhos. LASFAR, Instituto de Tecnologia em Farmacos. Laboratorio de Sintese de Fármacos. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Universidade Federal Fluminense. Faculdade de Farmácia. Laboratorio de Quimica Medicinal Computacional. Niterói, RJ, Brasil. | pt_BR |
| Affilliation | Universidade Federal Fluminense. Faculdade de Farmácia. Laboratorio de Quimica Medicinal Computacional. Niterói, RJ, Brasil. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Farmanguinhos. LASFAR, Instituto de Tecnologia em Farmacos. Laboratorio de Sintese de Fármacos. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Universidade do Esatdo do Rio de Janeiro. Instituto de Biologia Roberto Alcantara Gomes. Laboratorio de Interacao Tripanossomatideos e Vetores. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Universidade do Esatdo do Rio de Janeiro. Instituto de Biologia Roberto Alcantara Gomes. Laboratorio de Interacao Tripanossomatideos e Vetores. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Universidade do Esatdo do Rio de Janeiro. Instituto de Biologia Roberto Alcantara Gomes. Laboratorio de Interacao Tripanossomatideos e Vetores. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Universidade do Esatdo do Rio de Janeiro. Instituto de Biologia Roberto Alcantara Gomes. Laboratorio de Interacao Tripanossomatideos e Vetores. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Farmanguinhos. LASFAR, Instituto de Tecnologia em Farmacos. Laboratorio de Sintese de Fármacos. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Universidade do Estado do Rio de Janeiro. Instituto de Biologia Roberto Alcantara Gomes. Departamento de Biofísica e Biometria. Laboratorio de Mutagenese Ambiental. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Subject | Nitroimidazoles | pt_BR |
| Subject | Chagas disease | pt_BR |
| Subject | Trypanosoma cruzi | pt_BR |
| Subject | Genotoxic activity | pt_BR |
| Subject | Molecular modeling | pt_BR |
| xmlui.metadata.dc.subject.ods | 03 Saúde e Bem-Estar | |
