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Trypanocidal nitroimidazole derivatives: Relationships among chemical structure and genotoxic activity

Buschini, Annamaria ; Giordani, Federica ; de Albuquerque, Cristina Northfleet ; Pellacani, Claudia ; Pelosi, Giorgio ; Rossi, Carlo ; Zucchi, Tânia Maria Araújo Domingues ; Poli, Paola

Biochemical pharmacology, 2007-05, Vol.73 (10), p.1537-1547 [Periódico revisado por pares]

New York, NY: Elsevier Inc

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Título:
Trypanocidal nitroimidazole derivatives: Relationships among chemical structure and genotoxic activity
Autor: Buschini, Annamaria ; Giordani, Federica ; de Albuquerque, Cristina Northfleet ; Pellacani, Claudia ; Pelosi, Giorgio ; Rossi, Carlo ; Zucchi, Tânia Maria Araújo Domingues ; Poli, Paola
Assuntos: 5-Nitromegazol ; Benznidazole ; Biological and medical sciences ; Cell Survival - drug effects ; Cell Survival - physiology ; Comet assay ; DNA Damage - drug effects ; DNA Fragmentation - drug effects ; Humans ; Leukocytes - cytology ; Leukocytes - drug effects ; Medical sciences ; Nitroimidazoles - pharmacology ; Oxidatively damaged DNA ; Pharmacology. Drug treatments ; Thiadiazole-5-nitrofuran ; Thiosemicarbazone ; Trypanocidal Agents - pharmacology ; Trypanosoma
É parte de: Biochemical pharmacology, 2007-05, Vol.73 (10), p.1537-1547
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
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Descrição: 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).
Editor: New York, NY: Elsevier Inc
Idioma: Inglês

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Trypanocidal nitroimidazole derivatives: Relationships among chemical structure and genotoxic activity

Buschini, Annamaria ; Giordani, Federica ; de Albuquerque, Cristina Northfleet ; Pellacani, Claudia ; Pelosi, Giorgio ; Rossi, Carlo ; Zucchi, Tânia Maria Araújo Domingues ; Poli, Paola

New York, NY: Elsevier Inc

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