Síntese de compostos bioativos e sondas fluorescentes contendo boro com aplicação contra Mycobacterium tuberculosis
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Data
2022-06-08
Autores
Prates, João Lucas Bruno
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Universidade Estadual Paulista (Unesp)
Resumo
A tuberculose (TB) é uma doença infecciosa transmitida por micobactérias do complexo Mycobacterium tuberculosis, sendo a principal espécie a M. tuberculosis (Mtb). No ano de 2020, foram notificados cerca de 10 milhões de casos, com 1,5 milhão de óbitos, por todo mundo. O tratamento de primeira linha é realizado com os seguintes fármacos: isoniazida, rifampicina, etambutol e pirazinamida. Entretanto, com o surgimento de cepas multirresistentes a fármacos (MDR-TB) e extensivamente resistente a fármacos (XDR-TB) a busca de novos compostos mais efetivos e seguros para o tratamento da TB se tornou uma emergência de Saúde Pública. Estudos demostram que derivados de ácidos borônicos, como benzoboroxois, se apresentam como promissores agentes anti-Mtb, principalmente contra cepas resistentes. Um dos exemplos, é o composto GSK656, descrito em 2017 por pesquisadores da empresa farmacêutica GlaxoSmithKline (GSK) que apresentou potente atividade anti-MTB contra cepas multi-resistentes. Além disso, pequenas moléculas contendo boro, denominadas como BODIPY, tem propriedades fluorescentes que são capazes de ligar-se em proteínas alvo e produzir fluorescência, se tornando uma ferramenta essencial para investigação do alvo de compostos bioativos, bem como contribuir com os estudos farmacocinéticos. Nosso grupo de pesquisa tem trabalhado na síntese de derivados benzofuroxânicos, devido sua atividade promissora anti-MTB. Dessa forma, este trabalho consiste na otimização estrutural de derivados benzofuroxanos aplicando a estratégia de substituição bioisostérica deste grupo pelo benzoboroxol e ácido borônico, além de núcleos BODIPYs. Assim, neste trabalho foram sintetizados derivados de ácidos borônicos inéditos (30-41), com rendimentos variando entre 22% a 62%, bem como dois derivados benzoboroxois inéditos (45 e 46), com rendimentos entre 31% e 15%, respectivamente. Ademais, foram sintetizados três núcleos BODIPYs (47-49). Os compostos finais (30-41 e 45) foram submetidos a ensaios para avaliar seus efeitos antimicobacterianos usando cepas de MTB H37Rv. Apenas o composto 30 apresentou atividade com valor de CIM90 igual a 23,79 μg/mL. Os demais apresentam CIM90 superior a 25,00 μg/mL, sendo considerado inativos contra M. tuberculosis. Um estudo, para determinação do coeficiente de partição (clog P) foi realizado com auxílio do programa pkCSM, revelando que os derivados ácidos borônicos e benzoboroxois, apresentam menor clog P, em comparação com seus respectivos benzofuroxânos, o que pode justificar a baixa atividade e/ou a inatividade destes compostos.
Tuberculosis (TB) is an infectious disease transmitted by mycobacteria of the Mycobacterium tuberculosis complex, the main species being M. tuberculosis (MTB). In 2020, about 10 million cases were reported, with 1.5 million deaths, worldwide. First-line treatment is performed with the following drugs: isoniazid, rifampicin, ethambutol and pyrazinamide. However, with the emergence of multidrug-resistant (MDR-TB) and extensively drug-resistant (XDR-TB) strains, the search for new, more effective and safer compounds for the treatment of TB has become a Public Health emergency. Studies show that boronic acid derivatives, such as benzoboroxols, are promising anti-MTB agents, especially against resistant strains. One of the examples is the compound GSK656, described in 2017 by researchers from the pharmaceutical company GlaxoSmithKline (GSK) that showed potent anti-MTB activity against multi- resistant strains. Furthermore, small boron-containing molecules, termed as BODIPY, have fluorescent properties that can bind to target proteins and produce fluorescence, making them an essential tool for investigation of the target of bioactive compounds, as well as pharmacokinetic studies. Our research group has been working on the synthesis of benzofuroxane derivatives, due to their promising anti- MTB activity. Thus, this work consists of the structural optimization of benzofuroxane derivatives applying the strategy of bioisosteric substitution of this group by benzoboroxol and boronic acid, in addition to BODIPYs nuclei. Thus, in this work, unpublished boronic acid derivatives (30-41) were synthesized, with yields ranging from 22% to 62%, as well as two unpublished benzoboroxoyl derivatives (45 and 46), with yields between 31% and 15%, respectively. In addition, three BODIPY nuclei were synthesized (47-49).Final compounds (30-41 and 45) were subjected to antimycobacterial assay using MTB H37Rv strains. Only compound 30 showed activity with an MIC90 value equal to 23.79 μg/mL, the others showed an MIC90 greater than 25.00 μg/mL, being considered inactive for M. tuberculosis. A study to determine the partition coefficient (clog P) was carried out with the aid of the pkCSM program, which revealed that boronic acids and benzoboroxoyls have lower clog P compared to their respective benzofuroxanes, which may explain the low activity and/or inactivity of these compounds.
Tuberculosis (TB) is an infectious disease transmitted by mycobacteria of the Mycobacterium tuberculosis complex, the main species being M. tuberculosis (MTB). In 2020, about 10 million cases were reported, with 1.5 million deaths, worldwide. First-line treatment is performed with the following drugs: isoniazid, rifampicin, ethambutol and pyrazinamide. However, with the emergence of multidrug-resistant (MDR-TB) and extensively drug-resistant (XDR-TB) strains, the search for new, more effective and safer compounds for the treatment of TB has become a Public Health emergency. Studies show that boronic acid derivatives, such as benzoboroxols, are promising anti-MTB agents, especially against resistant strains. One of the examples is the compound GSK656, described in 2017 by researchers from the pharmaceutical company GlaxoSmithKline (GSK) that showed potent anti-MTB activity against multi- resistant strains. Furthermore, small boron-containing molecules, termed as BODIPY, have fluorescent properties that can bind to target proteins and produce fluorescence, making them an essential tool for investigation of the target of bioactive compounds, as well as pharmacokinetic studies. Our research group has been working on the synthesis of benzofuroxane derivatives, due to their promising anti- MTB activity. Thus, this work consists of the structural optimization of benzofuroxane derivatives applying the strategy of bioisosteric substitution of this group by benzoboroxol and boronic acid, in addition to BODIPYs nuclei. Thus, in this work, unpublished boronic acid derivatives (30-41) were synthesized, with yields ranging from 22% to 62%, as well as two unpublished benzoboroxoyl derivatives (45 and 46), with yields between 31% and 15%, respectively. In addition, three BODIPY nuclei were synthesized (47-49).Final compounds (30-41 and 45) were subjected to antimycobacterial assay using MTB H37Rv strains. Only compound 30 showed activity with an MIC90 value equal to 23.79 μg/mL, the others showed an MIC90 greater than 25.00 μg/mL, being considered inactive for M. tuberculosis. A study to determine the partition coefficient (clog P) was carried out with the aid of the pkCSM program, which revealed that boronic acids and benzoboroxoyls have lower clog P compared to their respective benzofuroxanes, which may explain the low activity and/or inactivity of these compounds.
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Palavras-chave
Tuberculose, Mycobacterium tuberculosis, Química farmacêutica, Corantes fluorescentes, Síntese orgânica