化学
广告
虚拟筛选
对接(动物)
IC50型
酶
立体化学
药物发现
选择性
单胺氧化酶B
药理学
组合化学
生物化学
体外
医学
护理部
单胺氧化酶
催化作用
作者
Esther del Olmo,Bianca Barboza,María Delgado‐Esteban,Nerea Escala,Daniel Jiménez-Blasco,José Luis López-Pérez,Laura Cillero de la Fuente,Elías Quezada,Javier Munín,Dolores Viña,Juan P. Bolaños,Arturo San Feliciano
标识
DOI:10.1016/j.bioorg.2024.107255
摘要
Monoaminooxidases (MAOs) are important targets for drugs used in the treatment of neurological and psychiatric disorders and particularly on Parkinsońs Disease (PD). Compounds containing a trans-stilbenoid skeleton have demonstrated good selective and reversible MAO-B inhibition. Here, twenty-two (Z)-3-benzylidenephthalides (benzalphthalides, BPHs) displaying a trans-stilbenoid skeleton have been synthesised and evaluated as inhibitors of the MAO-A and MAO-B isoforms. Some BPHs have selectively inhibited MAO-B, with IC50 values ranging from sub-nM to μM. The most potent compound with IC50 = 0.6 nM was the 3́,4́-dichloro-BPH 16, which showed highly selective and reversible MAO-B inhibitory activity. Furthermore, the most selective BPHs displayed a significant protection against the apoptosis, and mitochondrial toxic effects induced by 6-hydroxydopamine (6OHDA) on SH-SY5Y cells, used as a cellular model of PD. The results of virtual binding studies on the most potent compounds docked in MAO-B and MAO-A were in agreement with the potencies and selectivity indexes found experimentally. Additionally, related to toxicity risks, drug-likeness and ADME properties, the predictions found for the most relevant BPHs in this research were within those ranges established for drug candidates.
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