Departamento de Química Orgánica, Facultad de Farmacia, Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain.
Bioorg Med Chem Lett. 2011 Jul 15;21(14):4224-7. doi: 10.1016/j.bmcl.2011.05.074. Epub 2011 May 30.
With the aim of finding the structural features for the human MAO inhibitory activity and selectivity, in the present communication we report the synthesis, pharmacological evaluation and a comparative study of a new series of 3-phenylcoumarins (compounds 1-4) and 3-benzoylcoumarins (compounds 5-8). A bromo atom and a methoxy/hydroxy substituent were introduced in these scaffolds, at six and eight positions of the coumarin moiety, respectively. The synthesized compounds 1-8 were evaluated as MAO-A and B inhibitors using R-(-)-deprenyl and iproniazide as reference compounds. The presence or absence of a carbonyl group between the coumarin and the phenyl substituent in 3 position remarks, respectively, the MAO-A or MAO-B inhibitory activity. Some of the new compounds showed MAO-B inhibitory activities in the low nanomolar range. Compound 2 (IC(50)=1.35nM) showed higher inhibitory activity than the R-(-)-deprenyl (IC(50)=19.60nM) and higher MAO-B selectivity, with more than 74,074-fold inhibition level, respecting to the MAO-A isoform.
为了寻找人类 MAO 抑制活性和选择性的结构特征，在本研究中，我们报告了一系列新的 3-苯基色酮（化合物 1-4）和 3-苯甲酰基色酮（化合物 5-8）的合成、药理学评价和比较研究。在色酮部分的 6 位和 8 位，这些支架上分别引入了一个溴原子和一个甲氧基/羟基取代基。合成的化合物 1-8 被用作 MAO-A 和 B 的抑制剂，使用 R-(-)-deprenyl 和异丙烟肼作为参考化合物。3 位色酮和苯基取代基之间羰基的存在或不存在分别表明 MAO-A 或 MAO-B 抑制活性。一些新化合物表现出低纳摩尔范围内的 MAO-B 抑制活性。化合物 2（IC50=1.35nM）对 MAO-B 的抑制活性高于 R-(-)-deprenyl（IC50=19.60nM），并且对 MAO-A 同工酶的选择性更高，抑制水平超过 74074 倍。
