Análise da atividade in vitro, in vivo e do mecanismo de ação de compostos benzofuroxanos frente à Mycobacterium tuberculosis.
Carregando...
Data
2022-09-27
Autores
Título da Revista
ISSN da Revista
Título de Volume
Editor
Universidade Estadual Paulista (Unesp)
Resumo
A importância do estudo de novos fármacos para o tratamento da tuberculose se justifica por essa ser uma das doenças infecciosas mais mortais no mundo. O aparecimento de cepas resistentes aos fármacos é uma preocupação constante que apenas pode ser diminuída por meio do estudo de novas moléculas e melhores esquemas terapêuticos. Neste projeto avaliamos 18 novos compostos benzofuroxanos com potencial inibitório contra o Mycobacterium tuberculosis. Dos 18 inicialmente avaliados, 11 foram selecionados por apresentarem valores de concentração inibitória mínima (CIM90) < 5 M e índices de seletividade > 10. Esses 11 compostos foram avaliados frente 10 isolados clínicos resistentes de M. tuberculosis, bactérias em estado intramacrofágico e quanto ao espectro de atividade. Todos os benzofuroxanos foram ativos contra isolados clínicos resistentes, apresentaram boa atividade frente bactérias intramacrofágicas e foram classificados como compostos de espectro de ação estreito. Os 2 melhores compostos selecionados de acordo com o potencial frente a isolados resistentes (TBs 10 e 13) foram avaliados em experimento de infecção e tratamento in vivo com camundongos Balb/c. Os resultados obtidos foram promissores, demonstrando efeito inibitório sobre o crescimento bacteriano além da comprovação da não-toxicidade e biodisponibilidade. Também apresentaram efeito sinérgico in vitro quando associados com a rifampicina (fármaco da terapia de TB). Finalmente, o composto líder selecionado no experimento in vivo (TB 10) foi avaliado quanto ao seu potencial inibitório frente bombas de efluxo, não sendo um inibidor dessa classe de proteínas. Efeitos da exposição do M. tuberculosis ao TB 10 também foram morfologicamente observados por meio de microscopia eletrônica de varredura, observando-se alterações de parede características de estresse celular e um mutante resistente foi identificado para posterior análise genotípica por meio de sequenciamento. Concluímos que a síntese dessa nova série de compostos culminando na escolha do benzofuroxano TB 10 foi significativa visto que conseguimos encontrar uma nova molécula com forte atividade inibitória in vitro e in vivo, alta segurança e biodisponibilidade além de potencial sinérgico com outros fármacos da terapia já utilizados o que aponta para um potencial novo composto indicado para o tratamento da tuberculose.
The importance of studying new drugs for the treatment of tuberculosis is justified by the fact that this is one of the deadliest infectious diseases in the world. The emergence of drugresistant strains is a constant concern that can only be reduced through the study of new molecules and better therapeutic regimens. In this project we evaluated 18 new benzofuroxane compounds withpotential against Mycobacterium tuberculosis. Of the 18 initially evaluated, 11 were selected for having minimum inhibitory concentration (MIC90) values < 5 M and selectivity indices > 10. These 11 compounds were evaluated against 10 resistant clinical isolates of M. tuberculosis, bacteria in an intramacrophagic state and activity spectrum. All benzofuroxanes were active against resistant isolates, showed activity against intramacrophagic bacteria and were classified as compounds with a narrow spectrum of action. The 2 compounds selected according to their potential against resistant isolates (TBs 10 and 13) were evaluated in an in vivo model of infection with Balb/c mice. The results obtained were very promising, demonstrating a good inhibitory effect on bacterial growth, in addition to proving non-toxicity and good bioavailability. They also showed synergistic effect in vitro when associated with rifampicin (TB therapy drug). Finally, the compound selected in the in vivo experiment (TB 10) was evaluated for its inhibitory potential against efflux pumps, not being an inhibitor of this class of proteins. Effects of exposure of M. tuberculosis to TB 10 were also morphologically observed by means of scanning electron microscopy, observing cell wall changes characteristic of cellular stress and a resistant mutant was identified for further genotypic analysis by means of sequencing. We conclude that the synthesis of this new series of compounds culminating in benzofuroxane TB 10 was very significant since we were able to find a new molecule with strong inhibitory activity in vitro and in vivo, high safety and bioavailability in addition to synergistic potential with other drugs in the therapy already used, which points to a potential new compound indicated for the treatment of tuberculosis.
The importance of studying new drugs for the treatment of tuberculosis is justified by the fact that this is one of the deadliest infectious diseases in the world. The emergence of drugresistant strains is a constant concern that can only be reduced through the study of new molecules and better therapeutic regimens. In this project we evaluated 18 new benzofuroxane compounds withpotential against Mycobacterium tuberculosis. Of the 18 initially evaluated, 11 were selected for having minimum inhibitory concentration (MIC90) values < 5 M and selectivity indices > 10. These 11 compounds were evaluated against 10 resistant clinical isolates of M. tuberculosis, bacteria in an intramacrophagic state and activity spectrum. All benzofuroxanes were active against resistant isolates, showed activity against intramacrophagic bacteria and were classified as compounds with a narrow spectrum of action. The 2 compounds selected according to their potential against resistant isolates (TBs 10 and 13) were evaluated in an in vivo model of infection with Balb/c mice. The results obtained were very promising, demonstrating a good inhibitory effect on bacterial growth, in addition to proving non-toxicity and good bioavailability. They also showed synergistic effect in vitro when associated with rifampicin (TB therapy drug). Finally, the compound selected in the in vivo experiment (TB 10) was evaluated for its inhibitory potential against efflux pumps, not being an inhibitor of this class of proteins. Effects of exposure of M. tuberculosis to TB 10 were also morphologically observed by means of scanning electron microscopy, observing cell wall changes characteristic of cellular stress and a resistant mutant was identified for further genotypic analysis by means of sequencing. We conclude that the synthesis of this new series of compounds culminating in benzofuroxane TB 10 was very significant since we were able to find a new molecule with strong inhibitory activity in vitro and in vivo, high safety and bioavailability in addition to synergistic potential with other drugs in the therapy already used, which points to a potential new compound indicated for the treatment of tuberculosis.
Descrição
Palavras-chave
Mycobacterium tuberculosis, Benzofuroxanos, Tuberculose