MAO Inhibitory Activity of 2-Arylbenzofurans versus 3-Arylcoumarins: Synthesis, invitro Study, and Docking Calculations
MAO Inhibitory Activity of 2-Arylbenzofurans versus 3-Arylcoumarins: Synthesis, invitro Study, and Docking Calculations
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DOI：
10.1002/cmdc.201300048
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发表时间：
2013-06-01
期刊：
影响因子：
3.4
通讯作者：
Delogu, Giovanna
中科院分区：
文献类型：
--
作者：
Ferino, Giulio;Cadoni, Enzo;Delogu, Giovanna
单胺氧化酶（Monoamine oxidase，MAO）是治疗神经系统疾病的重要药物靶点。一些3-芳基香豆素衍生物以前被描述为有趣的选择性单胺氧化酶-B抑制剂。在保留反式二苯乙烯结构的基础上，合成了一系列2-芳基苯并呋喃和相应的3-芳基香豆素衍生物，并评价了它们作为单胺氧化酶异构体MAO-A和MAO-B的抑制剂。一般而言，发现这两种类型的衍生物都是选择性的MAO-B抑制剂，IC 50值在纳摩尔至微摩尔范围内。5-硝基-2-（4-甲氧基苯基）苯并呋喃（8）是苯并呋喃系列中活性最高的化合物，具有单胺氧化酶-B选择性和可逆抑制作用（IC 50 = 140 nM）。3-（4-甲氧基苯基）-6-硝基香豆素（15）具有与化合物8相同的取代模式，被发现是香豆素系列中最具活性的MAO-B抑制剂（IC 50 = 3 nM）。然而，3-苯基香豆素14显示出相同范围内的活性（IC 50 = 6 nM），是可逆的，并且比化合物15的选择性高几倍。将最具活性的化合物对接到MAO-B和MAO-A结合口袋中的对接实验突出了衍生物类别（2-芳基苯并呋喃和3-芳基香豆素）之间的不同相互作用，并提供了关于酶抑制剂相互作用和这些支架的潜在治疗应用的新信息。
Monoamine oxidase (MAO) is an important drug target for the treatment of neurological disorders. Several 3-arylcoumarin derivatives were previously described as interesting selective MAO-B inhibitors. Preserving the trans-stilbene structure, a series of 2-arylbenzofuran and corresponding 3-arylcoumarin derivatives were synthesized and evaluated as inhibitors of both MAO isoforms, MAO-A and MAO-B. In general, both types of derivatives were found to be selective MAO-B inhibitors, with IC50 values in the nano- to micromolar range. 5-Nitro-2-(4-methoxyphenyl)benzofuran (8) is the most active compound of the benzofuran series, presenting MAO-B selectivity and reversible inhibition (IC50=140nM). 3-(4-Methoxyphenyl)-6-nitrocoumarin (15), with the same substitution pattern as that of compound 8, was found to be the most active MAO-B inhibitor of the coumarin series (IC50=3nM). However, 3-phenylcoumarin 14 showed activity in the same range (IC50=6nM), is reversible, and also severalfold more selective than compound 15. Docking experiments for the most active compounds into the MAO-B and MAO-A binding pockets highlighted different interactions between the derivative classes (2-arylbenzofurans and 3-arylcoumarins), and provided new information about the enzymeinhibitor interaction and the potential therapeutic application of these scaffolds.