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

• Published in: European journal of medicinal chemistry 2020-01, Vol.186, p.111887, Article 111887
• Main Authors: do Vale Chaves e Mello, Francisco, Castro Salomão Quaresma, Bruna Maria, Resende Pitombeira, Marcelly Cristina, Araújo de Brito, Monique, Farias, Patrícia Pereira, Lisboa de Castro, Solange, Salomão, Kelly, Silva de Carvalho, Alcione, Oliveira de Paula, Jéssica Isis, de Brito Nascimento, Suelen, Peixoto Cupello, Mauricio, Paes, Marcia Cristina, Boechat, Nubia, Felzenszwalb, Israel
• Format: Article
• Language: English
• Subjects: Animals; Antiprotozoal Agents - chemical synthesis; Antiprotozoal Agents - chemistry; Antiprotozoal Agents - pharmacology; Cell Proliferation - drug effects; Cell Survival - drug effects; Cells, Cultured; Chagas disease; Chlorocebus aethiops; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Genotoxic activity; Hep G2 Cells; Humans; Mice; Microbial Sensitivity Tests; Models, Molecular; Molecular modeling; Molecular Structure; Nitroimidazoles; Nitroimidazoles - chemical synthesis; Nitroimidazoles - chemistry; Nitroimidazoles - pharmacology; Nitroreductases - antagonists & inhibitors; Nitroreductases - metabolism; RAW 264.7 Cells; Salmonella enterica - drug effects; Structure-Activity Relationship; Trypanocidal Agents - chemical synthesis; Trypanocidal Agents - chemistry; Trypanocidal Agents - pharmacology; Trypanosoma cruzi; Trypanosoma cruzi - drug effects; Trypanosoma cruzi - enzymology
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2019.111887

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. [Display omitted] •Novel 4-nitroimidazoles were synthesized with a variety of hydrophobic groups.•Addition of hydrophobic groups improves greatly the anti-T. cruzi activity.•Compound 4 exhibited the highest trypanocidal activity.•Compounds 4, 5 and 11 induced cytotoxicity, mutagenicity and genotoxicity.•Compound 4 has relevant characteristics to bind to T. cruzi type I nitroreductase.