RESUMO
Development of effective vaccine candidates against tuberculosis is currently the most important challenge in the prevention of this disease since the BCG vaccine fails to guarantee a lifelong protection, while any other approved vaccine with better efficiency is still absent. The protective effect of the recombinant fusion protein ESAT6-CFP10-dIFN produced in a prokaryotic expression system (Escherichia coli) has been assessed in a guinea pig model of acute tuberculosis. The tested antigen comprises the Mycobacterium tuberculosis (Mtb) proteins ESAT6 and CFP10 as well as modified human γ-interferon (dIFN) for boosting the immune response. Double intradermal immunization of animals with the tested fusion protein (2 × 0.5 µg) induces a protective effect against subsequent Mtb infection. The immunized animals do not develop the symptoms of acute tuberculosis and their body weight gain was five times more as compared with the non-immunized-infected animals. The animal group immunized with this dose of antigen displays the minimum morphological changes in the internal organs and insignificant inflammatory lesions in the liver tissue, which complies with a decrease in the bacterial load in the spleen and average Mtb counts in macrophages.
RESUMO
Development of effective vaccine candidates against tuberculosis (TB) is currently the most important challenge in the prevention of this disease since the BCG vaccine fails to guarantee a lifelong protection, while any other approved vaccine with better efficiency is still absent. The protective effect of the recombinant fusion protein CFP10-ESAT6-dIFN produced in a prokaryotic expression system (Escherichia coli) has been assessed in a guinea pig model of acute TB. The tested antigen comprises the Mycobacterium tuberculosis (Mtb) proteins ESAT6 and CFP10 as well as modified human γ-interferon (dIFN) for boosting the immune response. Double intradermal immunization of guinea pigs with the tested fusion protein (2 × 0.5 µg) induces a protective effect against subsequent Mtb infection. The immunized guinea pigs do not develop the symptoms of acute TB and their body weight gain was five times more as compared with the non-immunized infected guinea pigs. The animal group immunized with this dose of antigen displays the minimum morphological changes in the internal organs and insignificant inflammatory lesions in the liver tissue, which complies with a decrease in the bacterial load in the spleen and average Mtb counts in macrophages.
Assuntos
Antígenos de Bactérias/imunologia , Proteínas de Bactérias/imunologia , Mycobacterium tuberculosis/imunologia , Vacinas contra a Tuberculose/imunologia , Tuberculose/prevenção & controle , Animais , Antígenos de Bactérias/administração & dosagem , Antígenos de Bactérias/genética , Proteínas de Bactérias/administração & dosagem , Proteínas de Bactérias/genética , Escherichia coli/genética , Escherichia coli/metabolismo , Feminino , Cobaias , Humanos , Imunização , Interferon gama/administração & dosagem , Interferon gama/genética , Interferon gama/imunologia , Mycobacterium tuberculosis/genética , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/imunologia , Tuberculose/imunologia , Tuberculose/microbiologia , Vacinas contra a Tuberculose/administração & dosagem , Vacinas contra a Tuberculose/genéticaRESUMO
A facile two-step synthetic approach to fluorinated and non-fluorinated 5-aryl-4-(5-nitrofuran-2-yl)-pyrimidines from readily available 5-bromo-4-(furan-2-yl)pyrimidine has been developed. All synthesized compounds were screened in vitro for their antibacterial activities against twelve various bacterial strains. It is demonstrated that some of these compounds exhibited significant antibacterial activities against strains Neisseria gonorrhoeae and Staphylococcus aureus, comparable and even higher with that commercial drug Spectinomycin.
Assuntos
Antibacterianos/farmacologia , Neisseria gonorrhoeae/efeitos dos fármacos , Nitrocompostos/farmacologia , Pirimidinas/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Antibacterianos/síntese química , Antibacterianos/química , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Estrutura Molecular , Nitrocompostos/síntese química , Nitrocompostos/química , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-AtividadeRESUMO
The first macrocyclic glycoterpenoids comprising glucosamine and diterpenoid isosteviol moieties were synthesized and evaluated for inhibition activity against Mycobacterium tuberculosis H37Rv.
Assuntos
Antituberculosos/síntese química , Diterpenos do Tipo Caurano/química , Glucosamina/química , Compostos Macrocíclicos/síntese química , Antituberculosos/química , Antituberculosos/farmacologia , Compostos Macrocíclicos/química , Compostos Macrocíclicos/farmacologia , Testes de Sensibilidade Microbiana , Estrutura Molecular , Mycobacterium tuberculosis/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
Various 5-(fluoroaryl)-4-(hetero)aryl substituted pyrimidines have been synthesized based on the Suzuki cross-coupling and nucleophilic aromatic substitution of hydrogen (SN(H)) reactions starting from commercially available 5-bromopyrimidine and their antitubercular activity against Mycobacterium tuberculosis H37Rv has been explored. The outcome of the study disclose that, some of the compounds have showed promising activity in micromolar concentration against Mycobacterium tuberculosis H37Rv, Mycobacterium avium, Mycobacterium terrae, and multidrug-resistant strains isolated from tuberculosis patients in Ural region (Russia). The data concerning the 'structure-activity' relationship for fluorinated compounds have been discussed.
Assuntos
Antituberculosos/síntese química , Antituberculosos/farmacologia , Flúor/química , Mycobacterium/efeitos dos fármacos , Pirimidinas/síntese química , Pirimidinas/farmacologia , Antituberculosos/química , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Testes de Sensibilidade Microbiana , Mycobacterium/classificação , Pirimidinas/químicaRESUMO
We have developed the practical method for polyfluorosalicylic acids synthesis via nucleophilic ortho-mono-substitution of fluorine atom with magnesium methoxide. We have managed to increase the yield of targeted polyfluorosalicylic acids from good to quantitative. We have studied the tuberculostatic activity of polyfluorosalicylic acids. It has been found that minimum inhibitory concentration (MIC) of compounds is from 0.7 to 6.5µg/mL depending on the structure.
Assuntos
Antituberculosos/química , Antituberculosos/farmacologia , Antituberculosos/síntese química , Técnicas de Química Sintética , Avaliação Pré-Clínica de Medicamentos/métodos , Flúor/química , Compostos de Magnésio/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Mycobacterium tuberculosis/efeitos dos fármacos , Ácido Salicílico/químicaRESUMO
Synthetic routes to novel N-(purin-6-yl)- and N-(2-aminopurin-6-yl) conjugates with amino acids and glycine-containing dipeptides were developed. In vitro testing of 42 new and known compounds made it possible to reveal a series of N-(purin-6-yl)- and N-(2-aminopurin-6-yl) conjugates exhibiting significant antimycobacterial activity against Mycobacterium tuberculosis H37Rv, Mycobacterium avium, Mycobacterium terrae, and multidrug-resistant M. tuberculosis strain isolated from tuberculosis patients in the Ural region (Russia). N-(2-Aminopurin-6-yl)- and N-(purin-6-yl)-glycyl-(S)-glutamic acids were the most active compounds.
Assuntos
Aminoácidos/farmacologia , Antibacterianos/farmacologia , Dipeptídeos/farmacologia , Mycobacterium/efeitos dos fármacos , Aminoácidos/síntese química , Aminoácidos/química , Antibacterianos/síntese química , Antibacterianos/química , Dipeptídeos/síntese química , Dipeptídeos/química , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Combination of the Suzuki cross-coupling and nucleophilic aromatic substitution of hydrogen (SN(H)) reactions proved to be a convenient method for the synthesis of C(4) and/or C(5) mono(thienyl) and di(thienyl) substituted pyrimidines from commercially available 5-bromopyrimidine. All new pyrimidines were found to be active in micromolar concentrations in vitro against H37Rv, avium, terrae, rifampicin and isoniazid-resistance strains of Mycobacterium tuberculosis. The data for acute in vivo toxicity in mice have been obtained for these compounds which appear to be promising antitubercular agents.
Assuntos
Antituberculosos/síntese química , Pirimidinas/síntese química , Ticrinafeno/química , Animais , Antituberculosos/química , Antituberculosos/farmacologia , Resistência a Medicamentos/efeitos dos fármacos , Concentração Inibidora 50 , Camundongos , Estrutura Molecular , Mycobacterium tuberculosis/efeitos dos fármacos , Pirimidinas/química , Pirimidinas/farmacologia , Relação Estrutura-AtividadeRESUMO
The Petasis reaction of 6-hydroxy adducts of 1-alkyl-2,3-dicyano-5-arylpyrazinium salts with trans-styrylboronic acids proved to proceed smoothly at room temperature to give the corresponding 5-(hetero)aryl-6-styryl substituted 1,6-dihydropyrazine derivatives. Also it has been found that C(6) unsubstituted 1,6-dihydro- or 1,4,5,6-tetrahydropyrazine derivatives can be easy prepared in high yields from the corresponding pyrazinium salts by reduction with triethylsilane. All synthesized compounds were screened in vitro for their antifungal activities against seven pathogenic fungal strains and antimycobacterial activities against Mycobacterium tuberculosis H37Rv, avium, terrae and multi-drug-resistant strains isolated from tuberculosis patients in the Ural region (Russia).
Assuntos
Antifúngicos/síntese química , Antituberculosos/síntese química , Nitrilas/química , Pirazinas/química , Antifúngicos/química , Antifúngicos/farmacologia , Antituberculosos/química , Antituberculosos/farmacologia , Cristalografia por Raios X , Farmacorresistência Bacteriana/efeitos dos fármacos , Fungos/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Conformação Molecular , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/isolamento & purificação , Nitrilas/síntese química , Nitrilas/farmacologia , Oxirredução , Pirazinamida/síntese química , Pirazinamida/química , Pirazinamida/farmacologia , Pirazinas/síntese química , Pirazinas/farmacologia , Silanos/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Combination of the Suzuki cross-coupling and nucleophilic aromatic substitution of hydrogen (SN(H)) reactions proved to be a convenient method for the synthesis of 5-styryl-4-(hetero)aryl substituted pyrimidines from commercially available 5-bromopyrimidine. All intermediate 5-bromo-4-(hetero)aryl substituted pyrimidines and also the targeted 5-styryl-4-(hetero)arylpyrimidines were found to be active in micromolar concentrations in vitro against Mycobacterium tuberculosis H37Rv, avium, terrae, and multi-drug-resistant strain isolated from tuberculosis patients in Ural region (Russia). It has been found that some of these compounds possess a low toxicity and have a bacteriostatic effect, comparable and even higher with that of first-line antituberculosis drugs.
