RESUMO
Nuclear factor kappa B (NF-κB) plays critical roles in the regulation of many pathophysiological processes, including inflammation and immune responses, cell growth and apoptosis. This DNA-binding protein receptor is considered an important molecular target to treat many diseases through host-directed therapy. In this line, several drugs containing thiophene cores have been extensively evaluated due to their ability to interfere on NF-κB translocation to the nucleus. In this work, assays using drug affinity responsive target stability (DARTS) revealed that the parent compound N-(Aryl)-2-thiophen-2-ylacetamide referred to as thiophenacetamide (TAA) specifically binds to the p65 subunit of the NF-κB. Since no experimental binding mode of TAA with p65 is available, we explored TAA within putative sites in silico to gain insights into its possible binding mode and behavior. The binding mode of TAA found in Site 1 formed hydrogen bonds with Lys37 and Asp125 on p65, important residues near DNA-binding region. Molecular dynamics simulations showed the stability of this mode of binding in contrast to the other also tested modes. Our results suggest that TAA binding could occur in regions close to residues responsible for DNA binding, increasing NF-κB protein rigidity and affecting the association between DNA and NF-κB. Communicated by Ramaswamy H. Sarma.
Assuntos
Acetamidas/química , Sistemas de Liberação de Medicamentos , NF-kappa B/genética , Fator de Transcrição RelA/genética , Acetamidas/uso terapêutico , Apoptose/genética , Sítios de Ligação/genética , Núcleo Celular/genética , Proliferação de Células/genética , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/genética , Humanos , Simulação de Dinâmica Molecular , NF-kappa B/química , Ligação Proteica/genética , Transdução de Sinais/genética , Fator de Transcrição RelA/químicaRESUMO
The present article describes a series of twenty-six N'-[(E)-(monosubstituted-benzylidene)]-2-pyrazinecarbohydrazide (4-29), which were synthesized and evaluated for their cell viabilities in non infected and infected macrophages with Mycobacterium bovis Bacillus Calmette-Guerin (BCG). Afterwards, the non-cytotoxic compounds (4, 6, 8, 15, 21, 23, 24, 27 and 28) were assessed against Mycobacterium tuberculosis ATCC 27294 using the micro plate Alamar Blue assay (MABA) and the activity expressed as the minimum inhibitory concentration (MIC) in microg/mL. The compounds 6, 23, 27 and 28 exhibited a significant activity (50-100 microg/mL) when compared with first line drugs such as pyrazinamide and were not cytotoxic in their respective MIC values.
Assuntos
Antibacterianos , Antituberculosos , Compostos de Benzilideno/síntese química , Hidrazinas/síntese química , Mycobacterium tuberculosis/efeitos dos fármacos , Pirazinamida/síntese química , Antibacterianos/síntese química , Antibacterianos/farmacologia , Antituberculosos/síntese química , Antituberculosos/farmacologia , Compostos de Benzilideno/química , Compostos de Benzilideno/farmacologia , Sobrevivência Celular , Desenho de Fármacos , Humanos , Hidrazinas/química , Hidrazinas/farmacologia , Macrófagos/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Pirazinamida/química , Pirazinamida/farmacologiaRESUMO
A series of 11 alpha,omega-diaminoalkanes, (H(2)N(CH(2))(n)NH(2), n=2-12) have been evaluated for their in vitro antibacterial activity against Mycobacterium tuberculosis H37Rv. Compounds, (H(2)N(CH(2))(n)NH(2), n=9-12), exhibited a very good activities in the range 2.50-3.12 microg/mL, which can be compared with that of the first line drug, ethambutol (3.12 microg/mL). These results and a preliminary QSAR study can be considered an important start point for the rational design of new leads for anti-TB compounds.
