title: Trypanocidal nitroimidazole derivatives: relationships among chemical structure and genotoxic activity.
abstract: Human American trypanosomiasis is resurgent in Latin Americans, and new drugs are urgently required as current medications suffer from a number of drawbacks. Some nitroheterocycles have been demonstrated to exert a potent activity against trypanosomes. However, host toxicity issues halted their development as trypanocides. As part of the efforts to develop new compounds in order to treat parasitic infections, it is important to define their structure-activity relationship. In this study, 5-nitromegazol and two of its analogues, 4-nitromegazol, and 1-methyl-5-nitro-2-imidazolecarboxaldehyde 5-nitroimidazole-thiosemicarbazone, were tested and compared for in vitro induction of DNA damage in human leukocytes by the comet assay, performed at different pHs to better identify the types of damage. Specific oxidatively generated damage to DNA was also measured by using the comet assay with endonucleases. DNA damage was found in 5-nitromegazol-treated cells: oxidative stress appeared as the main source of DNA damage. 4-Nitromegazol did not produce any significant effect, thus confirming that 4-nitroimidazoles isomers have no important biological activity. The 5-nitroimidazole-thiosemicarbazone induced DNA damage with a higher efficiency than 5-nitromegazol. The central role in the reduction process played by the acidic hydrazine proton present in the thiosemicarbazone group but not in the cyclic (thiadiazole) form can contribute to rationalise our results. Given its versatility, thiosemicarbazone moiety could be involved in different reactions with nitrogenous bases (nucleophilic and/or electrophilic attacks).
authors.affiliation: Dipartimento di Genetica, Biologia dei Microrganismi, Antropologia, Evoluzione, Università di Parma, Parco Area delle Scienze, Parma, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Buschini
authors.forename: Federica
authors.initials: F
authors.lastname: Giordani
authors.forename: Cristina Northfleet
authors.initials: CN
authors.lastname: de Albuquerque
authors.forename: Claudia
authors.initials: C
authors.lastname: Pellacani
authors.forename: Giorgio
authors.initials: G
authors.lastname: Pelosi
authors.forename: Carlo
authors.initials: C
authors.lastname: Rossi
authors.forename: Tânia Maria Araújo Domingues
authors.initials: TM
authors.lastname: Zucchi
authors.forename: Paola
authors.initials: P
authors.lastname: Poli
mesh_terms: D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004249:DNA Damage / Q000187:drug effects*; D053938:DNA Fragmentation / Q000187:drug effects*; D006801:Humans; D007962:Leukocytes / Q000166:cytology / Q000187:drug effects*; D009593:Nitroimidazoles / Q000494:pharmacology*; D014344:Trypanocidal Agents / Q000494:pharmacology*
chemical_list: D009593:Nitroimidazoles; D014344:Trypanocidal Agents