2. Academic Validation
  3. Novel nitroimidazole derivatives evaluated for their trypanocidal, cytotoxic, and genotoxic activities

Novel nitroimidazole derivatives evaluated for their trypanocidal, cytotoxic, and genotoxic activities

  • Eur J Med Chem. 2020 Jan 15:186:111887. doi: 10.1016/j.ejmech.2019.111887.
Francisco do Vale Chaves E Mello 1,  Bruna Maria Castro Salomão Quaresma 2,  Marcelly Cristina Resende Pitombeira 2,  Monique Araújo de Brito 3,  Patrícia Pereira Farias 3,  Solange Lisboa de Castro 4,  Kelly Salomão 4,  Alcione Silva de Carvalho 5,  Jéssica Isis Oliveira de Paula 6,  Suelen de Brito Nascimento 6,  Mauricio Peixoto Cupello 6,  Marcia Cristina Paes 6,  Nubia Boechat 7,  Israel Felzenszwalb 8
Affiliations

Affiliations

  • 1 Laboratorio de Mutagenese Ambiental, Departamento de Biofisica e Biometria, Instituto de Biologia Roberto Alcantara Gomes, UERJ, Rio de Janeiro, RJ, 20551-030, Brazil.
  • 2 Instituto de Ciencias Biomedicas, Programa de Pos-Graduacao Farmacologia e Quimica Medicinal, UFRJ, Rio de Janeiro, RJ, 21941-902, Brazil; Laboratorio de Sintese de Farmacos - LASFAR, Instituto de Tecnologia em Farmacos, Farmanguinhos-Fiocruz, Rio de Janeiro, RJ, 21041-250, Brazil.
  • 3 Laboratorio de Quimica Medicinal Computacional, Faculdade de Farmacia, Universidade Federal Fluminense, Niteroi, RJ, 24241-001, Brazil.
  • 4 Laboratorio de Biologia Celular, Instituto Oswaldo Cruz, Fundacao Oswaldo Cruz, IOC-Fiocruz, Rio de Janeiro, RJ, 21040-900, Brazil.
  • 5 Laboratorio de Sintese de Farmacos - LASFAR, Instituto de Tecnologia em Farmacos, Farmanguinhos-Fiocruz, Rio de Janeiro, RJ, 21041-250, Brazil.
  • 6 Laboratorio de Interacao Tripanossomatideos e Vetores, Instituto de Biologia Roberto Alcantara Gomes, UERJ, Rio de Janeiro, RJ, 20551-030, Brazil.
  • 7 Laboratorio de Sintese de Farmacos - LASFAR, Instituto de Tecnologia em Farmacos, Farmanguinhos-Fiocruz, Rio de Janeiro, RJ, 21041-250, Brazil. Electronic address: nubia.boechat@far.fiocruz.br.
  • 8 Laboratorio de Mutagenese Ambiental, Departamento de Biofisica e Biometria, Instituto de Biologia Roberto Alcantara Gomes, UERJ, Rio de Janeiro, RJ, 20551-030, Brazil. Electronic address: felzen@uerj.br.
PMID: 31787363 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-nitro-1H-imidazole-5-yl)-1H-1,2,3-triazole) was identified as the most potent against both the trypomastigote (IC50 = 5.4 μM) and amastigote (IC50 = 12.0 μM) forms of T. cruzi, showing activity in the same range as Bnz (IC50 = 8.8 and 8.7 μM, 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 π-π interactions between the nitroimidazole and the cofactor (flavin mononucleotide) of T.cruzi-nitroreductase (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.

Keywords

Chagas disease; Genotoxic activity; Molecular modeling; Nitroimidazoles; Trypanosoma cruzi.

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