Article
In vitro genotoxicity of nitroimidazoles as a tool in the search of new trypanocidal agents
Registro en:
VON TROMPOWSKY, Ana Claudia Manoel et al. In vitro genotoxicity of nitroimidazoles as a tool in the search of new trypanocidal agents. Memórias do Instituto Oswaldo Cruz, Rio de Janeiro, v. 114, p. 1-10, 2019.
0074-0276
10.1590/0074-02760190017
1678-8060
Autor
Von Trompowsky, Ana Claudia Manuel
Conde, Taline Ramos
Lemos, Renata Calil
Quaresma, Bruna Maria C. S.
Pitombeira, Marcelly Cristina S. R.
Carvalho, Alcione Silva de
Boechat, Núbia
Salomão, Kelly
Castro, Solange Lisboa de
Zamith, Helena Pereira da Silva
Resumen
Only benznidazole (Bnz) (1) and nifurtimox (Nfx) (2) are licensed for the treatment of Chagas disease although their safety and efficacy profile are far from ideal. Farmanguinhos from Fiocruz has developed seven nitroimidazole compounds (4-10) analogs of megazol (3). OBJECTIVES To evaluate whether the genotoxic effect of 3 was abolished in the seven nitroimidazoles (4-10) analogs using the in vitro alkaline comet assay (CA) and the in vitro cytokinesis-block micronucleus assay (CBMN) in whole human blood cells (WHBC) and correlate this effect with their trypanocidal activity using bloodstream trypomastigote forms of Trypanosoma cruzi.
METHODS The toxicity of 3-10 to WHBC in the in vitro CA was determined using the fluorescein diacetate/ethidium bromide assay. DNA damage in the in vitro CA was evaluated according to tail size in four classes (0-3) and methyl methane-sulfonate (MMS) was used as a positive control. The cytotoxicity of 3-10 to WHBC in the CBMN was measured using the cytokinesis-block proliferation index and the replication index. The number of the micronucleate cells in 2,000 binucleate cells by experimental
group was determined. Mitomycin C and N-deacetyl-N-methylcolchicine were used as positive controls. FINDINGS Compound 3 showed a significant DNA strand break effect through the in vitro CA and highly significant clastogenic and/or aneugenic effect in the CBMN. Compounds 5, 6, 8, 9 and 10 showed negative results in the CBMN and positive results in
the in vitro CA, while the inverse effect was observed for 4 and 7. MAIN CONCLUSIONS Compound 10 was the most promising to proceed with the development as a drug candidate in the treatment of Chagas disease showing absence of chromosomal cytogenetic damage and high activity against T. cruzi, about two times higher than 3 and the clinical drug 1.