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Sustainable Development Goals
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NOVEL NITROIMIDAZOLE DERIVATIVES EVALUATED FOR THEIR TRYPANOCIDAL, CYTOTOXIC, AND GENOTOXIC ACTIVITIES
Trypanosoma cruzi
Nitroimidazoles
Atividade genotóxica
Modelagem molecular
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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.
Keywords in Portuguese
Doença de ChagasTrypanosoma cruzi
Nitroimidazoles
Atividade genotóxica
Modelagem molecular
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