Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna , Via Belmeloro 6, I-40126 Bologna, Italy.
J Med Chem. 2014 Oct 23;57(20):8576-89. doi: 10.1021/jm5010804. Epub 2014 Oct 10.
We report the identification of multitarget anti-Alzheimer compounds designed by combining a naphthoquinone function and a tacrine fragment. In vitro, 15 compounds displayed excellent acetylcholinesterase (AChE) inhibitory potencies and interesting capabilities to block amyloid-β (Aβ) aggregation. The X-ray analysis of one of those compounds in complex with AChE allowed rationalizing the outstanding activity data (IC50 = 0.72 nM). Two of the compounds showed negligible toxicity in immortalized mouse cortical neurons Neuro2A and primary rat cerebellar granule neurons. However, only one of them was less hepatotoxic than tacrine in HepG2 cells. In T67 cells, both compounds showed antioxidant activity, following NQO1 induction. Furthermore, in Neuro2A, they were able to completely revert the decrease in viability induced by Aβ. Importantly, they crossed the blood-brain barrier, as demonstrated in ex vivo experiments with rats. When ex vivo results were combined with in vitro studies, these two compounds emerged to be promising multitarget lead candidates worthy of further pursuit.
我们报告了通过将萘醌功能和他克林片段结合设计的多靶抗阿尔茨海默病化合物的鉴定。在体外，有 15 种化合物表现出优异的乙酰胆碱酯酶（AChE）抑制活性和有趣的阻止淀粉样蛋白-β（Aβ）聚集的能力。其中一种化合物与 AChE 形成复合物的 X 射线分析，使我们能够合理地解释其出色的活性数据（IC50 = 0.72 nM）。两种化合物在永生化的小鼠皮质神经元 Neuro2A 和原代大鼠小脑颗粒神经元中显示出可忽略的毒性。然而，只有一种化合物在 HepG2 细胞中的肝毒性低于他克林。在 T67 细胞中，两种化合物在 NQO1 诱导后均显示出抗氧化活性。此外，在 Neuro2A 中，它们能够完全逆转 Aβ诱导的活力下降。重要的是，它们能够穿过血脑屏障，这在使用大鼠的离体实验中得到了证明。当将离体结果与体外研究相结合时，这两种化合物被认为是有前途的多靶先导候选物，值得进一步研究。
