RESUMO
In this study, the antimycobacterial activity of mono and di-substituted tetrazole and oxadiazole derivatives and their precursors was assayed on Mycobacterium tuberculosis H37Rv, and cytotoxicity was evaluated on J774 macrophages and on tumoral cell lines. Structure Activity Relationship (SAR) analysis was performed using Principal Component Analysis (PCA) to determine the relationship between these compounds and their biological activities.
Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Mycobacterium/efeitos dos fármacos , Oxidiazóis/síntese química , Oxidiazóis/farmacologia , Tetrazóis/síntese química , Tetrazóis/farmacologia , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Relação Estrutura-Atividade , Sais de Tetrazólio , TiazóisRESUMO
The antimycobacterial activity of nine biphenyl methanone (BPM) derivatives against standard strains of Mycobacterium kansasii, M. avium and M. malmoense was determined by colorimetric assay in microplates with the dye Alamar Blue. Acute toxicity of these compounds was also analyzed by determination of CO2 concentration in a respirometric assay using Escherichia coli. The compounds showed weak antimycobacterial activity with a minimal inhibitory concentration (MIC) over 0.038 mmol l-1 and no toxicity was found in E. coli up to 400 mmol l-1. No cytotoxicity was observed on V79 cells up to 0.35 mmol l-1 with 7 of the BPM derivatives, with two exceptions (X = SO2CH3, NO2) that showed some toxicity. The greatest antimycobacterial activity was observed with the SO2CH3 derivative and the application of Principal Component Analysis (PCA) showed a relationship between structure and antimycobacterial activity of the compounds. Two descriptors, nucleophilic superdelocalizability of carbon atom and pi-hydrophobic constant, were necessary to describe this relationship.
Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Compostos de Bifenilo/síntese química , Compostos de Bifenilo/farmacologia , Mycobacterium/efeitos dos fármacos , Animais , Antibacterianos/toxicidade , Antineoplásicos/toxicidade , Compostos de Bifenilo/toxicidade , Células CHO , Corantes , Cricetinae , Ensaios de Seleção de Medicamentos Antitumorais , Escherichia coli/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana , Vermelho Neutro , Ácidos Nucleicos/biossíntese , Sais de Tetrazólio , Tiazóis , Células Tumorais CultivadasRESUMO
Principal Component Analysis (PCA) and Artificial Neural Network (ANN) were used to analyze the relationship between the structure and the activities of a series of nine biphenyl-phenyl methanone derivatives against Mycobacterium tuberculosis in vitro. Both PCA and ANN were able to classify these derivatives in two categories: low active and highly active compounds. Empirical and theoretical descriptors were used in the classification process. The descriptors selected by PCA indicated that the reactivity plays an important role in the determination of antimycobacterial activity of biphenylphenyl methanone derivatives (BPM). The BPM showed a moderate activity against the M. tuberculosis strain tested with the exception of chloride-, bromide- and nitroderivatives (when X = Cl, Br, NO2) which were the most actives against M. tuberculosis in vitro among all the methanones studied.