Estudos in vitro e in vivo de compostos furoxânicos, benzofuroxânicos e quinoxalinas com potencial aplicação para o tratamento da tuberculose
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Data
2017-04-29
Autores
Souza, Paula Carolina de [UNESP]
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Universidade Estadual Paulista (Unesp)
Resumo
A busca por novos fármacos faz-se necessária sob dois principais pontos: a cura/tratamento do paciente pela melhora de qualidade de vida e a importância de tratalo a fim de eliminar focos de propagação das doenças infecto-contagiosas. A tuberculose (TB) se insere neste panorama, visto que é uma doença infecciosa que tem como principal patógeno o Mycobacterium tuberculosis (Mtb). A taxa de mortalidade da TB caiu 45% desde 1990 e o mundo estaria a caminho de atingir a meta global de redução de 50% até o ano de 2015. A última pesquisa conduzida no ano de 2015 mostrou 6,3 milhões de casos de TB notificados pelos programas nacionais da doença, dos quais 55% correspondem a casos de co-infecção TB-HIV. Uma recente problemática repercute: a resistência. Fato comprovado pela estimativa de 580.000 novos casos de TB-MDR no ano de 2015 comparados aos 480.000 casos registrados em 2014; e o relato de 9,7% desses casos serem na verdade TB-XDR. Baseado nesses dados epidemiológicos observamos a necessidade da busca de novos fármacos a fim de melhorar a terapia e consequentemente a qualidade de vida e cura dos pacientes. Nesse sentido, essa tese buscou investigar o potencial biológico de vinte e dois novos compostos n-óxidos: derivados furoxânicos, benzofuroxânicos e derivados quinoxalínicos; in vitro e in vivo. Investigamos também a segurança e dados preliminares ao mecanismo de ação. Os compostos demonstraram atividade (CIM90) entre 0,40 – 62 µM. Dentre todos os compostos n-óxidos estudados, o derivado benzofuroxânico 8 demonstrou-se mais promissor, com atividade frente ao Mtb com valores de CIM90 de 1,10 e 6,62 µM frente a bactéria no estado ativo e latente, respectivamente. A citotoxicidade frente à linhagem celular MRC-5 (IC50) foi obtida na concentração de 519,2 µM. Esse composto também apresentou atividade frente às cepas monorresistentes a importantes fármacos da terapia (isoniazida, rifampicina, moxifloxacina, bedaquilina, cicloserina e estreptomicina); assim como demostrou uma atividade intramacrofágica similar ao fármaco da terapia rifampicina – aproximadamente 90% de inibição para todas as concentrações testadas. Para os estudos in vivo (biodisponibilidade oral, tolerabilidade, infecção e tratamento) os compostos foram incorporados em microemulssão devido instabilidade em pH 1,0 e 9,0; mostrando-se biodisponíveis e toleráveis. Por fim, comprovamos o quanto essas classes são promissoras in vivo, três compostos (dois pertencentes ao grupo de derivados furoxânicos e um derivado de benzofuroxânico) esterilizaram a infecção pulmonar com Mtb de camundongos BALB/c. Apresentamos assim, três novos compostos com potencial para estudos clínicos e futuramente serem classes químicas presentes na terapia da doença.
The search for new drugs is necessary under two main points: the cure / treatment of the patient for the improvement of quality of life and the importance of treating it in order to eliminate outbreaks of the spread of infecto-contagious diseases. Tuberculosis (TB) is part of this scenario, since TB is an infectious disease with Mycobacterium tuberculosis (Mtb) as its main pathogen. The TB mortality rate has dropped by 45% since 1990 and the world is on track to meet the global 50% reduction target by 2015. The latest survey conducted in 2015 showed 6.3 million TB cases notified by national disease programs, of which 55% correspond to cases of HIV-TB co-infection. A recent problem has repercussions: resistance. This is proven by the estimated 580,000 new cases of MDRTB in 2015 compared to 480,000 cases in 2014; actually 9.7% of these cases are TBXDR. Based on these epidemiological data, we observed the need to search for new drugs in order to improve therapy and consequently the quality of life and cure of patients. In this sense, this thesis sought to investigate the biological potential in vitro and in vivo of twenty-two new n-oxide compounds: furoxanic, benzofuroxanic and quinoxaline derivatives. We also investigated the safety and preliminary data on the mechanism of action of these compounds. The compounds showed activity (MIC90) in a ranging 0.40 to 62 µM. Among all the n-oxide studied, the benzofuroxan (8) was more promising (MIC90 values of 1.10 and 6.62 μM against the active and latent bacteria, respectively; and cytotoxicity against the MRC-5 cell line (IC50) was obtained at the concentration of 519.2 μM). This compound also showed activity against the monoresistant strains of important drugs of the therapy (isoniazid, rifampicin, moxifloxacin, bedaquiline, cycloserine and streptomycin) as well as demonstrated an intramacrophagic activity similar to the drug of rifampicin therapy - approximately 90% inhibition at all concentrations tested. For in vivo studies (oral bioavailability, tolerability and treatment) the compounds were incorporated into microemulsion due to instability at pH 1.0 and 9.0; being bioavailable and tolerable. Finally, we verified how much these classes are promising in vivo. Three compounds (two belonging to the group of furoxanic derivatives and a benzofuroxanic derivative) sterilize pulmonary infection with Mtb of BALB / c mice. Thus, we present three new compounds with potential for clinical studies and in future being chemical classes present in the therapy of the disease.
The search for new drugs is necessary under two main points: the cure / treatment of the patient for the improvement of quality of life and the importance of treating it in order to eliminate outbreaks of the spread of infecto-contagious diseases. Tuberculosis (TB) is part of this scenario, since TB is an infectious disease with Mycobacterium tuberculosis (Mtb) as its main pathogen. The TB mortality rate has dropped by 45% since 1990 and the world is on track to meet the global 50% reduction target by 2015. The latest survey conducted in 2015 showed 6.3 million TB cases notified by national disease programs, of which 55% correspond to cases of HIV-TB co-infection. A recent problem has repercussions: resistance. This is proven by the estimated 580,000 new cases of MDRTB in 2015 compared to 480,000 cases in 2014; actually 9.7% of these cases are TBXDR. Based on these epidemiological data, we observed the need to search for new drugs in order to improve therapy and consequently the quality of life and cure of patients. In this sense, this thesis sought to investigate the biological potential in vitro and in vivo of twenty-two new n-oxide compounds: furoxanic, benzofuroxanic and quinoxaline derivatives. We also investigated the safety and preliminary data on the mechanism of action of these compounds. The compounds showed activity (MIC90) in a ranging 0.40 to 62 µM. Among all the n-oxide studied, the benzofuroxan (8) was more promising (MIC90 values of 1.10 and 6.62 μM against the active and latent bacteria, respectively; and cytotoxicity against the MRC-5 cell line (IC50) was obtained at the concentration of 519.2 μM). This compound also showed activity against the monoresistant strains of important drugs of the therapy (isoniazid, rifampicin, moxifloxacin, bedaquiline, cycloserine and streptomycin) as well as demonstrated an intramacrophagic activity similar to the drug of rifampicin therapy - approximately 90% inhibition at all concentrations tested. For in vivo studies (oral bioavailability, tolerability and treatment) the compounds were incorporated into microemulsion due to instability at pH 1.0 and 9.0; being bioavailable and tolerable. Finally, we verified how much these classes are promising in vivo. Three compounds (two belonging to the group of furoxanic derivatives and a benzofuroxanic derivative) sterilize pulmonary infection with Mtb of BALB / c mice. Thus, we present three new compounds with potential for clinical studies and in future being chemical classes present in the therapy of the disease.
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Palavras-chave
Tuberculose, Furoxanos, Benzofuroxanos, Quinoxalina, Novas moléculas, Tuberculosis, Furoxans, Benzofuroxans, Quinoxaline, New molecules