3-(E)-Styryl-2H-chromene derivatives as potent and selective monoamine oxidase B inhibitors.

A series of novel 3-(E)-styryl-2H-chromene derivatives were synthesized and their monoamine oxidase (MAO) A and B inhibitory activities were evaluated. All compounds exhibited no inhibitory activity towards MAO-A at 10 µM whereas compounds 1-5, 7, 9, 11-13, 15 and 16 showed strong inhibitory activity towards MAO-B at this concentration. Of these, compound 3, which contains fluorine at R3, showed the highest activity (IC50 = 10 nM), and is about 22-fold more potent than pargyline (used as a positive control). Quantitative structure-activity relationship (QSAR) analyses of 3-(E)-styryl-2H-chromene derivatives were conducted using Molecular Operating Environment (MOE). QSAR analyses of 3-(E)-styryl-2H-chromene derivatives with pIC50 values for MAO-B demonstrated that 140 descriptors showed significant correlations. The strongly correlated descriptors indicated that properties such as molecular shape, size, and hydrophobicity, as well as the functional groups, of 3-(E)-styryl-2H-chromene derivatives are important for their inhibitory activity. This is the first report identifying 3-(E)-styryl-2H-chromene derivatives as potent and selective MAO-B inhibitors. These results suggest that the 3-(E)-styryl-2H-chromene structure may be a useful scaffold for the design and development of novel monoamine oxidase inhibitors.

Quantitative Structure-Cytotoxicity Relationship of 3-Styryl-2H-chromenes.

BACKGROUND: Sixteen 3-styryl-2H-chromenes were subjected to quantitative structure-activity relationship analysis based on their cytotoxicity, tumor selectivity and anti-HIV activity, in order to find their new biological activities. MATERIALS AND METHODS: Cytotoxicity against four human oral squamous cell carcinoma (OSCC) cell lines, three mesenchymal and two epithelial normal oral cells was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method. Tumor-selectivity (TS) was evaluated by the ratio of the mean CC50 (50% cytotoxic concentration) against normal human oral cells to that against OSCC cell lines. Anti-HIV activity was evaluated by the ratio of CC50 to EC50 (50% cytoprotective concentration from HIV infection). Potency-selectivity expression (PSE) was determined by the ratio of TS/CC50 against OSCC. Physicochemical, structural and quantum-chemical parameters were calculated based on the conformations optimized by the LowModeMD method. RESULTS: All 3-styryl-2H-chromene derivatives showed relatively high tumor selectivity. Especially, the compound that has a methoxy group at 7-position of the chromene ring and chlorine at 4'-position of phenyl group in styryl moiety [ 12: ] showed the highest TS and PSE values, exceeding those of resveratrol, doxorubicin and 5-FU. All compounds showed no anti-HIV activity. Among 330 chemical descriptors, 8, 74 and 16 descriptors significantly correlated to the cytotoxicity of normal and tumor cells, and tumor-specificity, respectively. CONCLUSION: Multivariate statistics with chemical descriptors for molecular shape and flatness may be useful for the evaluation of tumor-specificity of 3-styryl-2H-chromenes.