RESUMO
Bacillus Calmette-Guérin (BCG) remains the only available and most widely administered vaccine against Mycobacterium tuberculosis (Mtb), yet it fails to protect vaccinated individuals either from primary infection or reactivation of latent tuberculosis (TB). Despite BCG's variable efficacy against TB, the fact remains that BCG imparts protection in children against the disease, indicating that BCG possesses a wide protective antigenic repertoire. However, its failure to impart protection in adulthood can be linked to its failure to generate long-lived memory response and elicitation of an inadequate immune response against latency-associated antigens. Therefore, to improve the protective efficacy of BCG, a novel vaccination strategy is required. Consequently, in the present study, we have exploited the vaccination potential of liposomized α-crystalline 1 (Acr1L), a latency-associated antigen to induce enduring protective immunity against Mtb in BCG-primed animals. It is noteworthy that an increase in the multi-functional [interferon (IFN)-γ(hi) /tumour necrosis factor (TNF)-α(hi) ] CD4 and CD8 T cells were observed in BCG-primed and Acr1L-boosted (BCG-Acr1L) animals, compared to BCG alone. Further, substantial expansion of both central memory (CD44(hi) /CD62L(hi) ) and effector memory (CD44(hi) /CD62L(lo) ) populations of CD4 and CD8 T cells was noted. Importantly, BCG-Acr1L exhibited significantly better protection than BCG, as evidenced by a reduction in the bacterial burden and histopathological data of the lungs. In essence, BCG-Acr1L could be a potent future vaccination strategy to reinvigorate BCG potency.
Assuntos
Vacina BCG/imunologia , Proteínas de Bactérias/imunologia , Imunização Secundária , Tuberculose Latente/prevenção & controle , Mycobacterium tuberculosis/efeitos dos fármacos , alfa-Cristalinas/imunologia , Animais , Vacina BCG/administração & dosagem , Vacina BCG/genética , Carga Bacteriana/efeitos dos fármacos , Proteínas de Bactérias/genética , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/microbiologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/microbiologia , Linfócitos T CD8-Positivos/patologia , Feminino , Receptores de Hialuronatos/genética , Receptores de Hialuronatos/imunologia , Memória Imunológica/efeitos dos fármacos , Imunofenotipagem , Interferon gama/biossíntese , Interferon gama/imunologia , Selectina L/genética , Selectina L/imunologia , Tuberculose Latente/imunologia , Tuberculose Latente/microbiologia , Tuberculose Latente/patologia , Lipossomos/química , Lipossomos/imunologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/microbiologia , Pulmão/patologia , Camundongos , Mycobacterium bovis/química , Mycobacterium bovis/imunologia , Mycobacterium tuberculosis/crescimento & desenvolvimento , Mycobacterium tuberculosis/imunologia , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/imunologia , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/imunologia , alfa-Cristalinas/genéticaRESUMO
A series of novel N-aryl substituted thieno[2,3-d]pyrimidin-4(3H)-ones were designed and synthesized as potential inhibitors of chorismate mutase. Synthesis of this class of compounds was carried out by using Cu-mediated C-N bond forming reaction between thieno[2,3-d]pyrimidin-4(3H)-ones and aryl boronic acids. The reaction can be performed in an open flask as the conversion was found to be not sensitive to the presence of air or atmospheric moisture. A range of compounds were prepared by using this method and single crystal X-ray diffraction study was performed using a representative compound. In vitro pharmacological data of some of the compounds synthesized along with dose response studies using active molecules are presented. In silico interactions of these molecules with chorismate mutase are also presented.
Assuntos
Corismato Mutase/antagonistas & inibidores , Cobre/química , Inibidores Enzimáticos/farmacologia , Compostos Organometálicos/química , Pirimidinonas/farmacologia , Catálise , Corismato Mutase/genética , Corismato Mutase/metabolismo , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Modelos Moleculares , Estrutura Molecular , Mycobacterium tuberculosis/enzimologia , Pirimidinonas/síntese química , Pirimidinonas/química , Relação Estrutura-AtividadeRESUMO
Novel polysubstituted pyrroles have been designed and accessed via a one-pot multicomponent reaction followed by Pd-mediated C-C bond forming reactions. All the compounds synthesized were tested for their PDE4B inhibitory properties in vitro and two of them obtained via Heck reaction showed significant inhibition. The docking results suggested that these alkenyl derivatives containing ester moiety interact well with the PDE4B protein in silico where the ester carbonyl oxygen played a key role. The pyrrole framework presented here could be a new template for the identification of small molecule based novel inhibitors of PDE4. The single crystal X-ray data of a representative compound is presented.
Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Inibidores da Fosfodiesterase 4/química , Inibidores da Fosfodiesterase 4/farmacologia , Pirróis/química , Pirróis/farmacologia , Animais , Catálise , Linhagem Celular , Cristalografia por Raios X , Modelos Moleculares , Paládio/química , Relação Estrutura-AtividadeRESUMO
A number of 2-(1H-indol-3-yl)quinoline-3-carbonitrile derivatives were synthesized via AlCl(3)-mediated C-C bond forming reaction between 2-chloroquinoline-3-carbonitrile and various indoles. The methodology does not require any N-protection of the indoles employed and provided the corresponding products in good yields. The molecular structure of a representative compound was established unambiguously by single crystal X-ray diffraction and structural elaboration of a compound synthesized has been demonstrated. Many of these compounds synthesized showed PDE4 inhibitory properties in vitro. A brief structure-activity relationship studies within the series along with docking results of a representative compound (EC(50) â¼0.89 µM) is presented.
Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/química , Inibidores da Fosfodiesterase 4/síntese química , Quinolinas/química , Cloreto de Alumínio , Compostos de Alumínio/química , Sítios de Ligação , Carbono/química , Proliferação de Células/efeitos dos fármacos , Cloretos/química , Simulação por Computador , Cristalografia por Raios X , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Células HEK293 , Humanos , Indóis/química , Conformação Molecular , Inibidores da Fosfodiesterase 4/química , Inibidores da Fosfodiesterase 4/farmacologia , Quinolinas/síntese química , Quinolinas/farmacologiaRESUMO
A facile and catalyst free synthesis of 6H-1-benzopyrano[4,3-b]quinolin-6-ones has been accomplished via the reaction of 4-chloro-2-oxo-2H-chromene-3-carbaldehyde with various aromatic amines in the presence of ultrasound. Some of these compounds were converted to the corresponding 2-(3-(hydroxymethyl)quinolin-2-yl)phenols and further structure elaboration of a representative quinoline derivative is presented. Molecular structure of two representative compounds was confirmed by single crystal X-ray diffraction study. Many of these compounds were evaluated for their anti-proliferative properties in vitro against four cancer cell lines and several compounds were found to be active. Further in vitro studies indicated that inhibition of sirtuins could be the possible mechanism of action of these molecules.
Assuntos
Antineoplásicos/síntese química , Benzopiranos/química , Quinolinas/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Sítios de Ligação , Catálise , Domínio Catalítico , Linhagem Celular Tumoral , Simulação por Computador , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Conformação Molecular , Quinolinas/síntese química , Quinolinas/farmacologia , Sirtuína 1/química , SonicaçãoRESUMO
A rapid and direct access to N-aryl substituted fused triazinone derivatives has been accomplished via N-arylation of 1,2,3-triazin-4-one ring involving a Cu-mediated coupling between triazinone derivatives and aryl boronic acids. A combination of Cu(OAc)(2)-Et(3)N in 1,2-dichloroethane was found to be effective and various fused triazinone derivatives have been prepared by using this methodology. Molecular structure of a representative compound was confirmed by single crystal X-ray diffraction study. The scope and limitations of this reaction is discussed. Some of the compounds synthesized were tested for chorismate mutase inhibitory properties in vitro. The in vitro dose response study of an active compound is presented.
Assuntos
Corismato Mutase/antagonistas & inibidores , Cobre/química , Inibidores Enzimáticos/farmacologia , Compostos Organometálicos/química , Triazinas/farmacologia , Catálise , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Modelos Moleculares , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-Atividade , Triazinas/síntese química , Triazinas/químicaRESUMO
The title compound, C(26)H(24)N(2)O(2), was prepared from the reaction of 4-chloro-3-formyl-coumarin with p-methyl-benzyl-amine. Even though there are no strong and specific inter-actions in the crystal structure, the translationally related mol-ecules form chains along the b axis. The coumarin moieties are stacked through π-π inter-actions [centroid-centroid distance = 3.5275â (7)â Å], forming layers perpendicular to the stacking direction.