RESUMO
Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), is the infectious disease responsible for the highest number of deaths worldwide. Herein, 22 new N-oxide-containing compounds were synthesized followed by in vitro and in vivo evaluation of their antitubercular potential against Mtb. Compound 8 was found to be the most promising compound, with MIC90 values of 1.10 and 6.62 µM against active and nonreplicating Mtb, respectively. Additionally, we carried out in vivo experiments to confirm the safety and efficacy of compound 8; the compound was found to be orally bioavailable and highly effective, leading to a reduction of Mtb to undetectable levels in a mouse model of infection. Microarray-based initial studies on the mechanism of action suggest that compound 8 blocks translation. Altogether, these results indicate that benzofuroxan derivative 8 is a promising lead compound for the development of a novel chemical class of antitubercular drugs.
Assuntos
Antituberculosos/química , Antituberculosos/farmacologia , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Animais , Antituberculosos/síntese química , Antituberculosos/farmacocinética , Disponibilidade Biológica , Células CACO-2 , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/farmacocinética , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/efeitos dos fármacos , Óxidos/química , Análise Espectral/métodosRESUMO
Tuberculosis (TB) is an important infectious disease caused by Mycobacterium tuberculosis (Mtb) and responsible for thousands of deaths every year. Although there are antimycobacterial drugs available in therapeutics, just few new chemical entities have reached clinical trials, and in fact, since introduction of rifampin only two important drugs had reached the market. Pyrazinoic acid (POA), the active agent of pyrazinamide, has been explored through prodrug approach to achieve novel molecules with anti-Mtb activity, however, there is no activity evaluation of these molecules against non-replicating Mtb until the present. Additionally, pharmacokinetic must be preliminary evaluated to avoid future problems during clinical trials. In this paper, we have presented six POA esters as prodrugs in order to evaluate their anti-Mtb activity in replicating and non-replicating Mtb, and these showed activity highly influenced by medium composition (especially by albumin). Lipophilicity seems to play the main role in the activity, possibly due to controlling membrane passage. Novel duplicated prodrugs of POA were also described, presenting interesting activity. Cytotoxicity of these prodrugs set was also evaluated, and these showed no important cytotoxic profile.
Assuntos
Antituberculosos/farmacologia , Ésteres/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Pró-Fármacos/farmacologia , Pirazinamida/análogos & derivados , Animais , Antituberculosos/síntese química , Antituberculosos/toxicidade , Proliferação de Células/efeitos dos fármacos , Chlorocebus aethiops , Relação Dose-Resposta a Droga , Ésteres/síntese química , Ésteres/toxicidade , Concentração Inibidora 50 , Testes de Sensibilidade Microbiana , Viabilidade Microbiana/efeitos dos fármacos , Estrutura Molecular , Mycobacterium tuberculosis/crescimento & desenvolvimento , Pró-Fármacos/síntese química , Pró-Fármacos/toxicidade , Pirazinamida/síntese química , Pirazinamida/farmacologia , Pirazinamida/toxicidade , Relação Estrutura-Atividade , Células VeroRESUMO
Ethnobotanists often utilize predictive models to analyze the potential of indigenously used medicinal plants. The most common of these prognostic models is the informant consensus model. This study evaluates use of this model through the analytical ethnopharmacology of Manus Province, Papua New Guinea (PNG). The informant consensus model enables researchers to prioritize plants for pharmacognostic evaluation, based on the relative frequency of plants cited in anthropological interviews. Fieldwork on Manus Island, PNG, led to the identification of 43 species of plants used in traditional medicine for persistent respiratory symptoms. Plants were collected, dried, micro-extracted using a new technique generated in our laboratory, and evaluated in vitro against Mycobacterium tuberculosis. The results, in the form of IC(50) values and modified selectivity indices (SI), were compared to the results of the anthropological models of informant consensus, and statistically compared through linear regression and t-tests. Results were not statistically significant (alpha=0.1), leading to the conclusions that the informant consensus assumptions were inaccurate in predicting anti-mycobacterial activity among the Manus for anti-TB claims.