Laboratory of Bioorganic Chemistry, Department of Pharmaceutical Sciences, Faculty of Pharmacy and Pharmaceutical Sciences, Josai University; 1-1 Keyaki-dai, Sakado, Saitama 350-0295, Japan.
Laboratory of Bioorganic Chemistry, Department of Pharmaceutical Sciences, Faculty of Pharmacy and Pharmaceutical Sciences, Josai University; 1-1 Keyaki-dai, Sakado, Saitama 350-0295, Japan.
Bioorg Chem. 2018 Apr;77:436-442. doi: 10.1016/j.bioorg.2018.01.036. Epub 2018 Feb 7.
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 R, showed the highest activity (IC = 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 pIC 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.
一系列新型 3-(E)-苯乙烯基-2H-色烯衍生物被合成，并评估了它们对单胺氧化酶（MAO）A 和 B 的抑制活性。所有化合物在 10μM 时对 MAO-A 均没有抑制活性，而化合物 1-5、7、9、11-13、15 和 16 在该浓度下对 MAO-B 表现出强烈的抑制活性。其中，含有 R 位氟的化合物 3 表现出最高的活性（IC=10nM），比帕吉林（用作阳性对照）强约 22 倍。采用分子操作环境（MOE）对 3-(E)-苯乙烯基-2H-色烯衍生物进行了定量构效关系（QSAR）分析。对 MAO-B 的 pIC 值为 3-(E)-苯乙烯基-2H-色烯衍生物的 QSAR 分析表明，140 个描述符显示出显著的相关性。强相关的描述符表明，3-(E)-苯乙烯基-2H-色烯衍生物的分子形状、大小和疏水性以及官能团等性质对其抑制活性很重要。这是首次报道 3-(E)-苯乙烯基-2H-色烯衍生物是强效和选择性的 MAO-B 抑制剂。这些结果表明，3-(E)-苯乙烯基-2H-色烯结构可能是设计和开发新型单胺氧化酶抑制剂的有用支架。
