RESUMO
A series of 4-quinolylhydrazones was synthesized and tested in vitro against Mycobacterium tuberculosis. At a concentration of 6.25microg/mL, most of the newly synthesized compounds displayed 100% inhibitory activity against M. tuberculosis in cellular assays. Further screening allowed the identification of very potent antitubercular agents. Compound 4c was also tested in a time-course experiment and against mtb clinical isolates, displaying interesting results.
Assuntos
Antituberculosos/química , Hidrazonas/química , Animais , Antituberculosos/síntese química , Antituberculosos/farmacologia , Linhagem Celular , Chlorocebus aethiops , Hidrazonas/síntese química , Hidrazonas/farmacologia , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/efeitos dos fármacos , Relação Estrutura-Atividade , Células VeroRESUMO
Development of multigenic constructs expressing Mycobacterium tuberculosis (Mtb) antigens may be a strategy to obtain improved DNA vaccines against tuberculosis (TB). Several multigenic constructs expressing two or three Mtb antigens as fusion proteins were developed, both as tPA- and ubiquitin-fusion proteins. To demonstrate proper protein expression and intracellular turnover all multiantigens were tagged with the HA epitope and constructs were used to transfect rhabdomyosarcoma (RD) cells. Antigen expression was demonstrated by immunofluorescence using anti-HA antibodies. C57Bl/6 mice were immunized with selected constructs and protective activity was assessed following aerogenic challenge with Mtb. Several of these constructs induced a significant level of protection in the lung and in the spleen. Immunization with the construct expressing tPA85B-ES6 induced a level of protection that approached that provided by BCG. Immunization with a combination of these constructs induced levels of protection that were not superior to those elicited by a single combination, and immunization with a construct expressing five Mtb antigens could not provide an improved level of protection compared to tPA85B-ES6. We conclude that the activity of a DNA vaccine based on tPA85B-ES6 cannot be enhanced by broadening the antigen repertoire with other highly immunogenic secreted Mtb proteins.