RESUMO
Nitroimidazole PA-824 is part of an exciting new class of compounds currently undergoing clinical evaluation as novel TB therapeutics. The recently elucidated mechanism of action of PA-824 involves reduction of the nitroimidazole ring and subsequent nitric oxide release. The importance of this compound and its unique activity prompted us to explore how substitution of the nitroimidazole ring would affect electrochemical reduction and antitubercular activity. We prepared analogs of PA-824 with bromo, chloro, cyano, and amino substituents in the 5-position of the aromatic ring. We found that substitution of the imidazole ring greatly influences reduction and the stability of the corresponding nitro radical anion. Further, the antitubercular activities of the bromo and chloro analogs may indicate that an alternate nitroreductase pathway within Mycobacterium tuberculosis exists.
Assuntos
Antituberculosos/química , Antituberculosos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Nitroimidazóis/química , Nitroimidazóis/farmacologia , Eletroquímica , Humanos , Oxirredução , Tuberculose/tratamento farmacológicoRESUMO
In this work both the electrochemical behavior and the analysis of the hypnotic pyrazolopyrimidine derivative zaleplon were studied. Zaleplon in ethanol-0.1M Britton Robinson buffer solution (30-70) showed 2 irreversible, well-defined cathodic responses in the pH range of 2-12 using differential pulse polarography (DPP), tast polarography, and cyclic voltammetry. From chronocoulometric studies, it was possible to conclude that one electron was transferred in each reduction peak or wave. For analytical purposes, the DPP technique working at pH 4.5 for peak I was selected, which exhibited adequate repeatability, reproducibility, and selectivity. The recovery was 99.97 +/- 1.52%, and the detection and quantitation limits were 5.13 x 10(-7)M and 1.11 x 10(-6)M, respectively. The DPP method was applied successfully to the individual assay of capsules in order to verify the content uniformity of zaleplon. Treatment of the sample is not required because the excipients do not interfere, the method is not time consuming, and it is less expensive than column liquid chromatography.
Assuntos
Acetamidas/análise , Anticonvulsivantes/análise , Técnicas de Química Analítica/métodos , Polarografia/métodos , Pirimidinas/análise , Calibragem , Cápsulas , Cromatografia Líquida , Formas de Dosagem , Relação Dose-Resposta a Droga , Indústria Farmacêutica , Eletroquímica/métodos , Eletrodos , Temperatura Alta , Concentração de Íons de Hidrogênio , Modelos Químicos , Reprodutibilidade dos Testes , TemperaturaRESUMO
With the aim of determining the actual target(s) of nitro-group bearing compounds considered as possible leads for the development of drugs against Chagas' disease, we studied in parallel nitrofurans and nitroimidazoles. We investigated nine representative compounds for the following properties: efficacy on different Trypanosoma cruzi strains, redox cyclers, inhibition of respiration, production of corresponding nitroso derivatives and intracellular thiol scavengers. Our results indicate that nifurtimox and related compounds act as redox cyclers, whereas the most active in the series, the 5-nitroimidazole megazol essentially acts as thiol scavenger particularly for trypanothione, the cofactor for trypanothione reductase, an essential enzyme in the detoxification process.