A set of twenty-five thioxanthene-9-one and xanthene-9-one derivatives, that were previously shown to inhibit cholinesterases (ChEs) and amyloid β (Aβ₄₀) aggregation, were evaluated for the inhibition of tau protein aggregation. All compounds exhibited a good activity, and eight of them (5–8, 10, 14, 15 and 20) shared comparable low micromolar inhibitory potency versus Aβ₄₀ aggregation and human acetylcholinesterase (AChE), while inhibiting human butyrylcholinesterase (BChE) even at submicromolar concentration. Compound 20 showed outstanding biological data, inhibiting tau protein and Aβ₄₀ aggregation with IC₅₀ = 1.8 and 1.3 μM, respectively. Moreover, at 0.1–10 μM it also exhibited neuroprotective activity against tau toxicity induced by okadoic acid in human neuroblastoma SH-SY5Y cells, that was comparable to that of estradiol and PD38. In preliminary toxicity studies, these interesting results for compound 20 are somewhat conflicting with a narrow safety window. However, compound 10, although endowed with a little lower potency for tau and Aβ aggregation inhibition additionally demonstrated good inhibition of ChEs and rather low cytotoxicity. Compound 4 is also worth of note for its high potency as hBChE inhibitor (IC₅₀ = 7 nM) and for the three order of magnitude selectivity versus hAChE. Molecular modelling studies were performed to explain the different behavior of compounds 4 and 20 towards hBChE.

The observed balance of the inhibitory potencies versus the relevant targets indicates the thioxanthene-9-one derivatives as potential MTDLs for AD therapy, provided that the safety window will be improved by further structural variations, currently under investigation.

一组二十五种 thioxanthene-9-one 和 xanthene-9-one 衍生物，之前被证明可以抑制胆碱酯酶 (ChEs) 和淀粉样蛋白 β (Aβ 40 )_聚集，评估了对 tau 蛋白聚集的抑制作用。所有化合物均表现出良好的活性，其中八种（5-8、10、14、15和20 ）具有与Aβ 40聚集和人乙酰胆碱酯酶 ( AChE )相当的低微摩尔抑制效力_，同时抑制人丁酰胆碱酯酶 (BChE)，即使在亚微摩尔浓度。化合物20显示出突出的生物学数据，抑制 tau 蛋白和 Aβ ₄₀聚集与 IC ₅₀  = 1.8 和 1.3 μM，分别。此外，在 0.1–10 μM 时，它还表现出对人神经母细胞瘤 SH-SY5Y 细胞中由奥卡多酸诱导的 tau 毒性的神经保护活性，这与雌二醇和 PD38 相当。在初步毒性研究中，化合物20的这些有趣结果与狭窄的安全窗有些矛盾。然而，尽管化合物10对 tau 和 Aβ 聚集的抑制效力略低，但它还表现出对 ChEs 的良好抑制作用和相当低的细胞毒性。化合物4也因其作为h BChE 抑制剂的高效力而值得注意（IC ₅₀ = 7 nM) 和三个数量级的选择性与 h AChE。进行分子建模研究以解释化合物4和20对h BChE 的不同行为。

观察到的抑制效力与相关靶点的平衡表明，thioxanthene-9-one 衍生物是 AD 治疗的潜在 MTDL，前提是安全窗将通过进一步的结构变化得到改善，目前正在研究中。