Evaluation of Genotoxic Effects of New Molecules with Possible Trypanocidal Activity for Chagas Disease Treatment

Mello, F.V.C.; Carvalho, Alcione Silva de; Bastos, Mônica M.; Boechat, Núbia; Aiub, Cláudia Alessandra Fortes; Felzenszwalb, Israel

doi:10.1155/2013/287319

Cited by 7 publications

(8 citation statements)

References 25 publications

(24 reference statements)

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“…Our group has investigated new nitroimidazoles as trypanocidal agents and their mutagenic/genotoxic activities. We have observed that these activities do not only depend on the nitro group ( Boechat et al 2001 , Carvalho et al 2004 , 2006 , 2007 , 2008 , 2014 , Mello et al 2013 ). Encouraged by this observation, in the present work we evaluated the genotoxic, mutagenic and antitrypanocidal activities of nine nitroimidazoles (11-19) ( Fig.…”

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confidence: 83%

Studies of genotoxicity and mutagenicity of nitroimidazoles: demystifying this critical relationship with the nitro group

Boechat

Carvalho

Salomão

et al. 2015

Mem. Inst. Oswaldo Cruz

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Nitroimidazoles exhibit high microbicidal activity, but mutagenic, genotoxic and cytotoxic properties have been attributed to the presence of the nitro group. However, we synthesised nitroimidazoles with activity against the trypomastigotes of Trypanosoma cruzi, but that were not genotoxic. Herein, nitroimidazoles (11-19) bearing different substituent groups were investigated for their potential induction of genotoxicity (comet assay) and mutagenicity (Salmonella/Microsome assay) and the correlations of these effects with their trypanocidal effect and with megazol were investigated. The compounds were designed to analyse the role played by the position of the nitro group in the imidazole nucleus (C-4 or C-5) and the presence of oxidisable groups at N-1 as an anion receptor group and the role of a methyl group at C-2. Nitroimidazoles bearing NO2 at C-4 and CH3 at C-2 were not genotoxic compared to those bearing NO2 at C-5. However, when there was a CH3 at C-2, the position of the NO2 group had no influence on the genotoxic activity. Fluorinated compounds exhibited higher genotoxicity regardless of the presence of CH3 at C-2 or NO2 at C-4 or C-5. However, in compounds 11 (2-CH3; 4-NO2; N-CH2OHCH2Cl) and 12 (2-CH3; 4-NO2; N-CH2OHCH2F), the fluorine atom had no influence on genotoxicity. This study contributes to the future search for new and safer prototypes and provide.

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confidence: 83%

Studies of genotoxicity and mutagenicity of nitroimidazoles: demystifying this critical relationship with the nitro group

Boechat

Carvalho

Salomão

et al. 2015

Mem. Inst. Oswaldo Cruz

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Section: Discussionmentioning

confidence: 99%

“…It showed cytotoxic activity in the concentration of 50 μg/mL in TA98 and in the range of 1.0-50 μg/mL in TA100 and TA1535 strains 39 . Our results of the CBMN of 6 in WHBC, recommended by OECD (2016) 30 differed from those obtained by Mello et al 39 who showed a significant increase of MNC in RAW 264.7 cells at concentrations of 10 and 100 μg/mL when treated for a period six times higher than that used in our study.…”

Section: Discussionmentioning

confidence: 99%

“…In relation to compound 6, mutagenicity was reported in the Ames test in TA100 strain of Salmonella typhimurium at the highest tested concentration (50 μg/mL) in the absence and presence of S9 mixture 39 . It showed cytotoxic activity in the concentration of 50 μg/mL in TA98 and in the range of 1.0-50 μg/mL in TA100 and TA1535 strains 39 . Our results of the CBMN of 6 in WHBC, recommended by OECD (2016) 30 differed from those obtained by Mello et al 39 who showed a significant increase of MNC in RAW 264.7 cells at concentrations of 10 and 100 μg/mL when treated for a period six times higher than that used in our study.…”

Section: Discussionmentioning

confidence: 99%

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In vitro genotoxicity of nitroimidazoles as a tool in the search of new trypanocidal agents

Trompowsky

Conde

Lemos

et al. 2019

Mem. Inst. Oswaldo Cruz

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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.

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“…As the damage was significantly higher also in control samples, indicating that the S9 fraction displayed genotoxic properties, its use has been omitted from the following experiments. It has been previously recorded that the S9 fraction itself is able to induce 2–2.5 times more revertants in TA97 and TA98 lines using the Ames test (Mello et al ., ; Sauerborn Klobučar et al ., ). Cells with excessive DNA damage (>50%) that are usually considered as dead or dying cells (e.g.…”

Section: Discussionmentioning

confidence: 99%

Genomic and gene expression responses to genotoxic stress in PAC2 zebrafish embryonic cell line

Šrut

Bourdineaud

Štambuk

et al. 2015

J of Applied Toxicology

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PAC2 cell line is, along most of the developed zebrafish cell lines, poorly characterized concerning its response to genotoxicants. To define the PAC2 cell line response to different forms of genotoxic stress, we exposed the cells to model genotoxic agents (benzo[a]pyrene, B[a]P, and ethyl methanesulfonate) and subsequently monitored DNA damage and alterations by using the battery of tests, including the Comet assay, quantitative random-amplified polymorphic DNA and amplified fragment length polymorphism. The expression of several DNA repair (xpc, xpd, hr23b, rad51, msh2) and oxidative stress response (sod (Cu/Zn)) genes was monitored as well. To obtain an indication of the PAC2 cell line metabolizing capacity, the expression of genes belonging to cyp1, cyp2 and cyp3 families was assessed upon exposure to B[a]P. Genotoxic responses were observed in all the used methods, and quantitative random-amplified polymorphic DNA and amplified fragment length polymorphism proved to be more sensitive by revealing DNA alterations even when the Comet assay indicated lack of significant damage. The PAC2 cell line demonstrated basal and B[a]P-induced expression of several cyp genes, suggesting its ability to metabolize indirect acting xenobiotics to a certain point. Based on these results, PAC2 cells seem to be sensitive zebrafish in vitro model in the genotoxicity assessment of the direct acting genotoxicant; however, they are less sensitive toward the indirect acting genotoxicant due to their limited metabolizing properties.

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Evaluation of Genotoxic Effects of New Molecules with Possible Trypanocidal Activity for Chagas Disease Treatment

Cited by 7 publications

References 25 publications

Studies of genotoxicity and mutagenicity of nitroimidazoles: demystifying this critical relationship with the nitro group

Studies of genotoxicity and mutagenicity of nitroimidazoles: demystifying this critical relationship with the nitro group

In vitro genotoxicity of nitroimidazoles as a tool in the search of new trypanocidal agents

Genomic and gene expression responses to genotoxic stress in PAC2 zebrafish embryonic cell line

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