Histone deacetylase 6 (HDAC6) has drawn more and more attention for its potential application in Alzheimer's disease (AD) therapy. A series of tetrahydro--carboline (THC) hydroxamic acids with aryl linker were synthesized. In enzymatic assay, all compounds exhibited nanomolar IC values. The most promising compound preferentially inhibited HDAC6 (IC, 8.64 nM) with approximately 149-fold selectivity over HDAC1. Molecular simulation revealed that the hydroxamic acid of could bind to the zinc ion by a bidentate chelating manner. In vitro, induced neurite outgrowth of PC12 cells without producing toxic effects and showed obvious neuroprotective activity in a model of HO-induced oxidative stress.

中文翻译：

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四氢-β-咔啉支架的重新探索：发现具有神经突生长促进和神经保护活性的选择性组蛋白脱乙酰酶 6 抑制剂

组蛋白脱乙酰酶 6 (HDAC6) 因其在阿尔茨海默病 (AD) 治疗中的潜在应用而受到越来越多的关注。合成了一系列带有芳基连接基的四氢咔啉（THC）异羟肟酸。在酶测定中，所有化合物均表现出纳摩尔 IC 值。最有前途的化合物优先抑制 HDAC6（IC50，8.64 nM），选择性约为 HDAC1 的 149 倍。分子模拟表明异羟肟酸可以通过双齿螯合方式与锌离子结合。在体外，诱导 PC12 细胞的神经突生长，而不产生毒性作用，并在 H2O 诱导的氧化应激模型中表现出明显的神经保护活性。