Departamento de Química Orgánica, Facultad de Farmacia, Universidad de Santiago de Compostela, Santiago de Compostela, Spain.
Bioorg Med Chem Lett. 2010 Sep 1;20(17):5157-60. doi: 10.1016/j.bmcl.2010.07.013. Epub 2010 Jul 8.
With the aim to find out the structural features for the MAO inhibitory activity and selectivity, in the present communication we report the synthesis and pharmacological evaluation of a new series of bromo-6-methyl-3-phenylcoumarin derivatives (with bromo atom in both different benzene rings of the skeleton) with and without different number of methoxy substituent at the 3-phenyl ring. The methoxy substituents were introduced, in this new scaffold, in the meta and/or para positions of the 3-phenyl ring. The synthesized compounds 3-7 were evaluated as MAO-A and B inhibitors using R-(-)-deprenyl (selegiline) and iproniazide as reference inhibitors, showing, most of them, MAO-B inhibitory activities in the low nanomolar range. Compounds 4 (IC(50)=11.05 nM), 5 (IC(50)=3.23 nM) and 6 (IC(50)=7.12 nM) show higher activity than selegiline (IC(50)=19.60 nM) and higher MAO-B selectivity, with more than 9050-fold, 30,960-fold and 14,045-fold inhibition levels, with respect to the MAO-A isoform.
为了探究 MAO 抑制活性和选择性的结构特征，本研究报告了一系列新的溴代 6-甲基-3-苯基香豆素衍生物（骨架的两个苯环上均有溴原子）的合成和药理学评价，其中 3-苯基环上带有或不带有不同数目的甲氧基取代基。在这个新骨架中，甲氧基取代基被引入到 3-苯基环的间位和/或对位。所合成的化合物 3-7 被用作 MAO-A 和 B 的抑制剂，使用 R-(-)-deprenyl（司来吉兰）和异丙烟肼作为参考抑制剂，其中大多数化合物在低纳摩尔范围内显示出 MAO-B 抑制活性。化合物 4（IC50=11.05 nM）、5（IC50=3.23 nM）和 6（IC50=7.12 nM）的活性高于司来吉兰（IC50=19.60 nM），对 MAO-B 的选择性更高，对 MAO-A 同工酶的抑制水平分别超过 9050 倍、30960 倍和 14045 倍。
