RESUMO
Sunscreening chemicals protect against damage caused by sunlight most absorbing UVA or UVB radiations. In this sense, 2-(2'-hydroxyphenyl)benzoxazole derivatives with amino substituents in the 4' and 5' positions have an outstandingly high Sun Protection Factor and adequate photostability, but their toxicity is not yet known. This study aimed to evaluate the toxicity of three synthetic 2-(2'-hydroxyphenyl)benzoxazole derivatives for their possible application as sunscreens. In silico tools were used in order to assess potential risks regarding mutagenic, carcinogenic, and skin sensitizing potential. Bioassays were performed in L929 cells to assess cytotoxicity in MTT assay and genotoxic activities in the Comet assay and micronucleus test. Also, the Salmonella/microsome assay was performed to evaluate gene mutations. The in silico predictions indicate a low risk of mutagenicity and carcinogenicity of the compounds while the skin sensitizing potential was low or inconclusive. The 2-(4'-amino-2'-hydroxyphenyl)benzoxazol compound was the most cytotoxic and genotoxic among the compounds evaluated in L929 cells, but none induced mutations in the Salmonella/microsome assay. The amino substituted at the 4' position of the phenyl ring appears to have greater toxicological risks than substituents at the 5' position of 2-(phenyl)benzoxazole. The findings warrant further studies of these compounds in cosmetic formulations.
Assuntos
Benzoxazóis/toxicidade , Relação Quantitativa Estrutura-Atividade , Protetores Solares/toxicidade , Animais , Benzoxazóis/química , Carcinogênese/efeitos dos fármacos , Linhagem Celular , Ensaio Cometa , Dano ao DNA/efeitos dos fármacos , Camundongos , Testes para Micronúcleos , Testes de Mutagenicidade , Salmonella typhimurium/efeitos dos fármacos , Protetores Solares/químicaRESUMO
N-oxide derivatives compounds such as furoxan and benzofuroxan are promising scaffolds for designing of new antileishmanial drugs. A series of furoxan (1,2,5-oxadiazole 2-N-oxide) (compounds 4a-b, and 14a-f) and benzofuroxan (benzo[c][1,2,5]oxadiazole1-N-oxide) (compounds 8a-c) derivatives were evaluated against in vitro cultured L. infantum promastigotes and amastigotes. The compounds exhibited activity against promastigote and intracellular amastigote forms with EC50 values ranging from 2.9 to 71.2µM and 2.1 to 18.2µM, respectively. The most promising compound, 14e, showed good antileishmanial activity (EC50=3.1µM) against intracellular amastigote forms of L. infantum with a selectivity index, based on murine macrophages (SI=66.4), almost 3-times superior to that presented by the standard drug amphotericin B (AmpB). The efficacy of 14e to eliminate the parasites in vivo was also demonstrated. Treatment of L. infantum-infected hamsters with compound 14e at 3.0mg/Kg/day led to a meaningful reduction of parasite load in spleen (49.9%) and liver (54.2%), respectively; these data were corroborated by histopathological analysis, which also revealed reduction in the number of inflammatory cells in the liver of the treated animals. Moreover, histological analysis of the spleen and kidney of treated animals did not reveal alterations suggestive of toxic effects. The parasite load reduction might be related to NO production, since this molecule is a NO-donor. We observed neither side effects nor elevation of hepatic/renal biomarker levels in the plasma. The data herein presented suggest that the compound should be considered in the development of new drugs for treatment of visceral leishmaniasis.
Assuntos
Antiprotozoários/uso terapêutico , Benzoxazóis/uso terapêutico , Leishmania infantum/efeitos dos fármacos , Leishmaniose Visceral/tratamento farmacológico , Anfotericina B/farmacologia , Anfotericina B/uso terapêutico , Anfotericina B/toxicidade , Animais , Antiprotozoários/química , Antiprotozoários/farmacologia , Benzoxazóis/química , Benzoxazóis/farmacologia , Benzoxazóis/toxicidade , Biomarcadores/metabolismo , Cricetinae , Rim/efeitos dos fármacos , Rim/parasitologia , Rim/patologia , Rim/fisiopatologia , Leishmaniose Visceral/parasitologia , Fígado/efeitos dos fármacos , Fígado/parasitologia , Fígado/patologia , Fígado/fisiopatologia , Macrófagos/efeitos dos fármacos , Macrófagos/parasitologia , Macrófagos/patologia , Masculino , Camundongos , Óxido Nítrico/biossíntese , Baço/efeitos dos fármacos , Baço/parasitologia , Baço/patologia , Resultado do TratamentoRESUMO
5-Phenylethenylbenzofuroxans have displayed in vitro and in vivo activity against Trypanosoma cruzi, the etiologic agent of American Trypanosomiasis. On the basis of benzofuroxans pre-clinical studies we evaluated the potential of six 5-phenylethenyl derivatives to induce cytotoxicity, mutagenicity and genotoxicity using different in vitro models. Cytotoxic effects were evaluated using a set of cells, mammal pre-monocytic macrophages, V-79 lung fibroblast from Chinese hamster, and colorectal adenocarcinoma Caco-2 cells, in the MTT viability assay. Mutagenicity was tested in the Ames assay using Salmonella typhimurium TA98 strain with and without metabolic activation by S9-rat liver homogenate. The genotoxic potentials were evaluated with the alkaline single cell gel electrophoresis (comet assay) in V-79 cells. In view of the Ames test results we study whether the main mammals' phase I metabolites, the corresponding o-nitroanilines, are involved in the mechanism of mutagenicity. These metabolites are produced by NADPH-dependent enzymes in cytosol and by xanthine oxidase and cytochrome P450 in microsomes from rat liver. Among them, the electronic property of phenyl substituent seems to be responsible for this effect. It could be pointed out that the equimolecular mixture of compounds 1 and 2 (5E- and 5Z-(2-phenylethenyl)benzofuroxan, respectively) could be used in further clinical studies as anti-T. cruzi drug.
Assuntos
Benzoxazóis/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Mutagênicos/toxicidade , Tripanossomicidas/toxicidade , Animais , Benzoxazóis/farmacocinética , Biotransformação , Corantes , Ensaio Cometa , Cricetinae , Citosol/metabolismo , Feminino , Humanos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Testes de Mutagenicidade , Ratos , Ratos Wistar , Salmonella typhimurium/efeitos dos fármacos , Salmonella typhimurium/genética , Sais de Tetrazólio , Tiazóis , Tripanossomicidas/farmacocinéticaRESUMO
New benzofuroxans were developed and studied as antiproliferative Trypanosoma cruzi agents. Compounds displayed remarkable in vitro activities against different strains, Tulahuen 2, CL Brener and Y. Its unspecific cytotoxicity was evaluated using human macrophages being not toxic at a concentration at least 8 times, and until 250 times, that of its T. cruzi IC50. Some biochemical pathways were studied, namely parasite respiration, cysteinyl active site enzymes and reaction with glutathione, as target for the mechanism of action. Not only T. cruzi respiration but also Cruzipain or trypanothione reductase were not affected, however the most active derivatives, the vinylsulfinyl- and vinylsulfonyl-containing benzofuroxans, react with glutathione in a redox pathway. Furthermore, the compounds showed good in vivo activities when they were studied in an acute murine model of Chagas' disease. The compounds were able to reduce the parasite loads of animals with fully established T. cruzi infections.