In vitro genotoxicity of nitroimidazoles as a tool in the search of new trypanocidal agents
BACKGROUND 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 eval...
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| Format: | Article |
| Language: | English |
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Fundação Oswaldo Cruz (FIOCRUZ)
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| Series: | Memorias do Instituto Oswaldo Cruz |
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| Online Access: | http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0074-02762019000100335&lng=en&tlng=en |
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| author | Ana Claudia Manoel Von Trompowsky Taline Ramos Conde Renata Calil Lemos Bruna Maria CS Quaresma Marcelly Cristina SR Pitombeira Alcione Silva de Carvalho Núbia Boechat Kelly Salomão Solange Lisboa de Castro Helena Pereira da Silva Zamith |
| author_facet | Ana Claudia Manoel Von Trompowsky Taline Ramos Conde Renata Calil Lemos Bruna Maria CS Quaresma Marcelly Cristina SR Pitombeira Alcione Silva de Carvalho Núbia Boechat Kelly Salomão Solange Lisboa de Castro Helena Pereira da Silva Zamith |
| author_sort | Ana Claudia Manoel Von Trompowsky |
| collection | DOAJ |
| description | BACKGROUND 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. |
| first_indexed | 2024-03-12T07:37:39Z |
| format | Article |
| id | doaj.art-bd2b5ebd0e9e4ced8b7d4ac70f0f09b2 |
| institution | Directory Open Access Journal |
| issn | 1678-8060 |
| language | English |
| last_indexed | 2024-03-12T07:37:39Z |
| publisher | Fundação Oswaldo Cruz (FIOCRUZ) |
| record_format | Article |
| series | Memorias do Instituto Oswaldo Cruz |
| spelling | doaj.art-bd2b5ebd0e9e4ced8b7d4ac70f0f09b22023-09-02T21:28:41ZengFundação Oswaldo Cruz (FIOCRUZ)Memorias do Instituto Oswaldo Cruz1678-806011410.1590/0074-02760190017S0074-02762019000100335In vitro genotoxicity of nitroimidazoles as a tool in the search of new trypanocidal agentsAna Claudia Manoel Von TrompowskyTaline Ramos CondeRenata Calil LemosBruna Maria CS QuaresmaMarcelly Cristina SR PitombeiraAlcione Silva de CarvalhoNúbia BoechatKelly SalomãoSolange Lisboa de CastroHelena Pereira da Silva ZamithBACKGROUND 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.http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0074-02762019000100335&lng=en&tlng=engenotoxicitymutagenicitymegazolnitroimidazoles |
| spellingShingle | Ana Claudia Manoel Von Trompowsky Taline Ramos Conde Renata Calil Lemos Bruna Maria CS Quaresma Marcelly Cristina SR Pitombeira Alcione Silva de Carvalho Núbia Boechat Kelly Salomão Solange Lisboa de Castro Helena Pereira da Silva Zamith In vitro genotoxicity of nitroimidazoles as a tool in the search of new trypanocidal agents Memorias do Instituto Oswaldo Cruz genotoxicity mutagenicity megazol nitroimidazoles |
| title | In vitro genotoxicity of nitroimidazoles as a tool in the search of new trypanocidal agents |
| title_full | In vitro genotoxicity of nitroimidazoles as a tool in the search of new trypanocidal agents |
| title_fullStr | In vitro genotoxicity of nitroimidazoles as a tool in the search of new trypanocidal agents |
| title_full_unstemmed | In vitro genotoxicity of nitroimidazoles as a tool in the search of new trypanocidal agents |
| title_short | In vitro genotoxicity of nitroimidazoles as a tool in the search of new trypanocidal agents |
| title_sort | in vitro genotoxicity of nitroimidazoles as a tool in the search of new trypanocidal agents |
| topic | genotoxicity mutagenicity megazol nitroimidazoles |
| url | http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0074-02762019000100335&lng=en&tlng=en |
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