In vitro and in vivo chromosomal aberrations induced by megazol

Nesslany, Fabrice; S, Brugier; Mouriès, Marie-Annick; Curieux, Frank Le; Marzin, Daniel

doi:10.1016/j.mrgentox.2004.02.013

Cited by 39 publications

(26 citation statements)

References 24 publications

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“…Megazol has been described as a scavenger of trypanothione, the cofactor for trypanothione reductase (23,42). Despite its noteworthy trypanocidal activity, megazol development was discontinued due to reports of in vitro mutagenic and genotoxic effects (16,29,30). In attempting to circumvent this undesired profile, megazol analogues were synthesized, but none have been shown to be more potent than the prototype (3,6,11).…”

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confidence: 99%

In Vitro and In Vivo Activities of 1,3,4-Thiadiazole-2-Arylhydrazone Derivatives of Megazol against Trypanosoma cruzi

Salomão

Souza

Carvalho

et al. 2010

Antimicrob Agents Chemother

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From a series of 1,3,4-thiadiazole-2-arylhydrazone derivatives of megazol screened in vitro against Trypanosoma cruzi, eight (S1 to S8) were selected for in vivo screening by single-dose oral administration (200 mg/kg of body weight) to infected mice at 5 days postinfection (dpi). Based on significant decreases in both parasitemia levels and mortality rates, S2 and S3 were selected for further assays. Despite having no in vivo effect, S1 was included since it was 2-fold more potent against trypomastigotes than megazol in vitro. Trypomastigotes treated with S1, S2, or S3 showed alterations of the flagellar structure and of the nuclear envelope. When assayed on intracellular amastigotes, the selectivity index (SI) for macrophages was in the range of >27 to >63 and for cardiac cells was >32 for S1 and >48 for megazol. In noninfected mice, S1 did not alter the levels of glutamic oxalacetic transaminase (GOT), glutamate pyruvate transaminase (GPT), or urea. S2 led to an increase in GOT, S3 to increases in GOT and GPT, and megazol to an increase in GOT. Infected mice were treated with each derivative at 50 and 100 mg/kg from dpi 6 to 15: S1 did not interfere with the course of infection or reduce the number of inflammatory foci in the cardiac tissue, S2 led to a significant decrease of parasitemia, and S3 decreased mortality. There was no direct correlation between the in vitro effect on trypomastigotes and amastigotes and the results of the treatment in experimental models, as S1 showed a high potency in vitro while, in two different schemes of in vivo treatment, no decrease of parasitemia or mortality was observed.

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confidence: 99%

In Vitro and In Vivo Activities of 1,3,4-Thiadiazole-2-Arylhydrazone Derivatives of Megazol against Trypanosoma cruzi

Salomão

Souza

Carvalho

et al. 2010

Antimicrob Agents Chemother

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“…Some nitroheterocycles are known to have problems with genotoxicity (39,40). For example, the development of megazol as a potential treatment for HAT was halted due to its genotoxicity (25,(41)(42)(43). Therefore, we conducted a number of in vitro assays on WSP934 to profile any potential genotoxic liabilities.…”

Section: Resultsmentioning

confidence: 99%

Characterization of a Melamino Nitroheterocycle as a Potential Lead for the Treatment of Human African Trypanosomiasis

Giordani

Buschini

Baliani

et al. 2014

Antimicrob Agents Chemother

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dThis paper reports an evaluation of a melamino nitroheterocycle, a potential lead for further development as an agent against human African trypanosomiasis (HAT). Studies on its efficacy, physicochemical and biopharmaceutical properties, and potential for toxicity are described. The compound previously had been shown to possess exceptional activity against Trypanosoma brucei in in vitro assays comparable to that of melarsoprol. Here, we demonstrate that the compound also was curative in the stringent acute mouse model T. brucei rhodesiense STIB 900 when given intraperitoneally at 40 mg/kg of body weight. Nevertheless, activity was only moderate when the oral route was used, and no cure was obtained when the compound was tested in a stage 2 rodent model of infection. Genotoxic profiling revealed that the compound induces DNA damage by a mechanism apparently independent from nitroreduction and involving the introduction of base pair substitutions (Ames test), possibly caused by oxidative damage of the DNA (comet test). No significant genotoxicity was observed at the chromosome level (micronucleus assay). The lack of suitable properties for oral and central nervous system uptake and the genotoxic liabilities prevent the progression of this melamine nitroheterocycle as a drug candidate for HAT. Further modification of the compound is required to improve the pharmacokinetic properties of the molecule and to separate the trypanocidal activity from the toxic potential.

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“…Yellow solid; mp 218-219 °C; yield 62%; (9). Yellow solid; mp 145-146 °C; yield 71%; (11). Gray solid; mp 213 °C; yield 45%; (12 …”

Section: -Methyl-5-nitro-2'-(4-nitrophenyl)-5'-phenyl-1h3'h-24'-bimentioning

confidence: 99%

“…Megazol has been described as a scavenger of trypanothione, the cofactor for trypanothione reductase [8,9]. Despite its noteworthy trypanocidal activity, megazol development was discontinued due to reports of its in vitro mutagenic and genotoxic effects [10][11][12]. To circumvent this undesirable profile, there have been numerous efforts to obtain megazol analogues [13][14][15][16][17].…”

Section: Introductionmentioning

confidence: 99%

Article Synthesis and Trypanocidal Activity of Novel 2,4,5-Triaryl-N-Hydroxylimidazole Derivatives

et al. 2013

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Herein, we report the design, synthesis and trypanocidal activity of some novel trisubstituted imidazole derivatives. These heterocyclic derivatives were structurally planned by exploring the concept of molecular hybridisation between two arylhydrazones derived from megazol, which has potent trypanocidal activity. The trypanocidal activity of these triarylimidazole derivatives was evaluated against infective trypomastigote forms of OPEN ACCESSMolecules 2013, 18 3446T. cruzi and the derivative 2'-(4-bromophenyl)-1-methyl-5'-phenyl-1H,3'H-2,4'-biimidazol-3'-ol showed moderate biological activity (IC 50 = 23.9 µM) when compared to benznidazole, a standard trypanocidal drug. These compounds did not present cytotoxic effects at concentrations near the trypanocidal IC 50 , being considered a good starting point for the development of new anti-Chagas drug candidates.

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In vitro and in vivo chromosomal aberrations induced by megazol

Cited by 39 publications

References 24 publications

In Vitro and In Vivo Activities of 1,3,4-Thiadiazole-2-Arylhydrazone Derivatives of Megazol against Trypanosoma cruzi

In Vitro and In Vivo Activities of 1,3,4-Thiadiazole-2-Arylhydrazone Derivatives of Megazol against Trypanosoma cruzi

Characterization of a Melamino Nitroheterocycle as a Potential Lead for the Treatment of Human African Trypanosomiasis

Article Synthesis and Trypanocidal Activity of Novel 2,4,5-Triaryl-N-Hydroxylimidazole Derivatives

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