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A series of twenty-six methoxylated and methylated <i>N</i>-aryl-1-hydroxynaphthalene- 2-carboxanilides was prepared and characterized as potential anti-invasive agents. The molecular structure of <i>N</i>-(2,5-dimethylphenyl)-1-hydroxynaphthalene-2-carboxamide as a model compound was determined by single-crystal X-ray diffraction. All the analysed compounds were tested against the reference strain <i>Staphylococcus aureus</i> and three clinical isolates of methicillin-resistant <i>S.</i> <i>aureus</i> as well as against <i>Mycobacterium tuberculosis</i> and <i>M. kansasii</i>. In addition, the inhibitory profile of photosynthetic electron transport in spinach (<i>Spinacia oleracea</i> L.) chloroplasts was specified. In vitro cytotoxicity of the most effective compounds was tested on the human monocytic leukaemia THP-1 cell line. The activities of <i>N</i>-(3,5-dimethylphenyl)-, <i>N</i>-(3-fluoro-5-methoxy-phenyl)- and <i>N</i>-(3,5-dimethoxyphenyl)-1-hydroxynaphthalene-2-carbox- amide were comparable with or even better than the commonly used standards ampicillin and isoniazid. All promising compounds did not show any cytotoxic effect at the concentration &gt;30 &#181;M. Moreover, an in silico evaluation of clogP features was performed for the entire set of the carboxamides using a range of software lipophilicity predictors, and cross-comparison with the experimentally determined lipophilicity (log <i>k</i>), in consensus lipophilicity estimation, was conducted as well. Principal component analysis was employed to illustrate noticeable variations with respect to the molecular lipophilicity (theoretical/experimental) and rule-of-five violations. Additionally, ligand-oriented studies for the assessment of the three-dimensional quantitative structure&#8722;activity relationship profile were carried out with the comparative molecular surface analysis to determine electron and/or steric factors that potentially contribute to the biological activities of the investigated compounds.