Planejamento, síntese e avaliação anti-Mycobacterium tuberculosis de novos derivados benzofuroxanos e nitroimidazooxazinas úteis para o tratamento da tuberculose multirresistente
Carregando...
Data
2021-02-01
Autores
Fernandes, Guilherme Felipe dos Santos
Título da Revista
ISSN da Revista
Título de Volume
Editor
Universidade Estadual Paulista (Unesp)
Resumo
Ainda que avanços tenham sido alcançados nos últimos anos para o tratamento da tuberculose (TB), enormes desafios como o surgimento de cepas resistentes tornam cada vez mais distantes o cumprimento das metas de eliminação da doença. Segundo a Organização Mundial de Saúde (OMS), no ano de 2018 foram diagnosticados cerca de 10 milhões de novos casos e registrados 1,2 milhão de mortes. Dos novos casos, 484 mil pacientes apresentavam TB multirresistente aos fármacos (MDR-TB) ou TB extensivamente resistente aos fármacos (XDR-TB) tornando o tratamento ainda mais demorado e desafiador. Nos últimos anos, intensos esforços realizados pelo nosso grupo de pesquisa permitiram por meio de uma rede de investigação nacional e internacional, a descoberta de protótipos com potente atividade anti-Mycobacterium tuberculosis (Mtb), inclusive contra cepas MDR-TB e XDR-TB. Destes, destaca-se o derivado benzofuroxano denominado BZ8, inibidor de síntese de proteínas, que durante o tratamento de animais infectados com o bacilo reduziu a zero as unidades formadoras de colônias nos pulmões dos animais, efeito não observado para nenhum dos fármacos atualmente disponíveis. Desde então, estudos de relação-estrutura atividade permitiram a identificação de padrões estruturais necessários para manutenção da atividade anti-Mtb. Neste trabalho, realizamos a sintese e avaliação biologica de duas novas séries de compostos planejados a partir do BZ8. A 1ª série comtemplou 27 novos compostos. A maioria dos compostos apresentaram algum grau de atividade anti-Mtb. Os compostos (GF1), (GF3), (GF10), (GF12), (GF14), (GF16) e (GF19) foram os mais promissores da série, apresentando valores de concentração inibitoria minima (CIM90) abaixo de 3,0 µM. Além disso, os compostos não apresentaram citotoxicidade nas linhagens celulares avaliadas. Os compostos mais promissores foram selecionados para avaliação contra cepas de MDR-TB. De maneira geral, os compostos apresentaram valores de CIM90 abaixo de 5 µM. Os compostos (GF3) e (GF16) foram particularmente os mais promissores dentro da série com valores de CIM90 abaixo de 1 µM para a maioria dos isolados MDR-Mtb testados. A 2ª série compreendeu 10 novos derivados de nitroimidazooxazina. Os compostos não apresentaram citotoxicidade nas linhagens celulares avaliadas. Ensaios biologicos para determinar a atividade anti-Mtb dos compostos da 2ª série estão em curso. Em conclusão, os novos derivados benzofuroxanos identificados neste trabalho se apresentam como uma nova classe de compostos promissores úteis para o tratamento de MDR-TB e XDR-TB.
Although advances have been made in recent years for the treatment of tuberculosis (TB), enormous challenges such as the emergence of resistant strains make it increasingly difficult to meet the goals of eliminating the disease. According to the World Health Organization (WHO), in 2018, about 10 million new cases were reported and 1.2 million deaths were recorded. Of the new cases, 484,000 patients had multidrug-resistant TB (MDR-TB) or extensively drugresistant TB (XDR-TB) making treatment even more time-consuming and challenging. In the past, intense efforts made by our research group have enabled, through a national and international research network, the discovery of prototypes with potent anti-Mycobacterium tuberculosis (Mtb) activity, including against MDR-TB and XDR-TB strains. Of these, the benzofuroxan derivative named BZ8 is highlighted, a protein synthesis inhibitor, which during the treatment of animals infected with Mtb reduced the colony-forming units in the animals' lungs to zero, an effect, not observed for any of the drugs currently available. Since then, structure-activity-relationship studies have allowed the identification of structural patterns necessary to maintain anti-Mtb activity. In this thesis, we carried out the synthesis and biological evaluation of two new series of compounds designed from BZ8. The 1st series included 27 new compounds. Most compounds showed some degree of anti-Mtb activity. The compounds (GF1), (GF3), (GF10), (GF12), (GF14), (GF16) and (GF19) were the most promising in the series, with minimum inhibitory concentration values (MIC90) below 3.0 µM. In addition, the compounds did not show cytotoxicity in the cell lines evaluated. The most promising compounds were selected for evaluation against MDR-TB strains. In general, compounds showed MIC90 values below 5 µM. The compounds (GF3) and (GF16) were particularly the most promising within the series with MIC90 values below 1 µM for most of the MDR-Mtb strains tested. The 2nd series covered 10 new nitroimidazooxazine derivatives. The compounds did not show cytotoxicity in the cell lines evaluated. Biological tests to determine the anti-Mtb activity of 2nd sieres compounds are underway. In conclusion, the new benzofuroxan derivatives identified in this work are presented as a new class of promising compounds useful for the treatment of MDR-TB and XDR-TB.
Although advances have been made in recent years for the treatment of tuberculosis (TB), enormous challenges such as the emergence of resistant strains make it increasingly difficult to meet the goals of eliminating the disease. According to the World Health Organization (WHO), in 2018, about 10 million new cases were reported and 1.2 million deaths were recorded. Of the new cases, 484,000 patients had multidrug-resistant TB (MDR-TB) or extensively drugresistant TB (XDR-TB) making treatment even more time-consuming and challenging. In the past, intense efforts made by our research group have enabled, through a national and international research network, the discovery of prototypes with potent anti-Mycobacterium tuberculosis (Mtb) activity, including against MDR-TB and XDR-TB strains. Of these, the benzofuroxan derivative named BZ8 is highlighted, a protein synthesis inhibitor, which during the treatment of animals infected with Mtb reduced the colony-forming units in the animals' lungs to zero, an effect, not observed for any of the drugs currently available. Since then, structure-activity-relationship studies have allowed the identification of structural patterns necessary to maintain anti-Mtb activity. In this thesis, we carried out the synthesis and biological evaluation of two new series of compounds designed from BZ8. The 1st series included 27 new compounds. Most compounds showed some degree of anti-Mtb activity. The compounds (GF1), (GF3), (GF10), (GF12), (GF14), (GF16) and (GF19) were the most promising in the series, with minimum inhibitory concentration values (MIC90) below 3.0 µM. In addition, the compounds did not show cytotoxicity in the cell lines evaluated. The most promising compounds were selected for evaluation against MDR-TB strains. In general, compounds showed MIC90 values below 5 µM. The compounds (GF3) and (GF16) were particularly the most promising within the series with MIC90 values below 1 µM for most of the MDR-Mtb strains tested. The 2nd series covered 10 new nitroimidazooxazine derivatives. The compounds did not show cytotoxicity in the cell lines evaluated. Biological tests to determine the anti-Mtb activity of 2nd sieres compounds are underway. In conclusion, the new benzofuroxan derivatives identified in this work are presented as a new class of promising compounds useful for the treatment of MDR-TB and XDR-TB.
Descrição
Palavras-chave
Química medicinal, Anti-infecciosos, Síntese orgânica, Tuberculose, Farmacorresistência bacteriana