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

2019; Elsevier BV; Volume: 186; Linguagem: Inglês

10.1016/j.ejmech.2019.111887

1768-3254

Francisco do Vale Chaves e Mello, Bruna Maria Castro Salomão Quaresma, Marcelly Cristina Resende Pitombeira, Monique Araújo de Brito, Patrícia Pereira Farias, Solange L. de Castro, Kelly Salomão, Alcione Silva de Carvalho, Jéssica Isis Oliveira Paula, Suelen de Brito Nascimento, Mauricio Peixoto Cupello, Márcia Cristina Paes, Núbia Boechat, Israel Felzenszwalb,

Bioactive Compounds and Antitumor Agents

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.