Alzheimer’s disease (AD) is the most common form of dementia that affects more than 40 million people around the world. The incidence is expected to rapidly increase due to the lack of any effective treatment. In previous work we synthesized a family of five ionophoric polyphenols (compounds 1–5) that targeted important aspects related to AD, such as the toxic aggregation of amyloid-β peptides, the production of reactive oxygen species, or the excessive presence of Cu²⁺ ions. Here, in order to gain insights into their potential therapeutic value, we have tested the ability of compounds 1–5 to cross the blood–brain barrier (BBB), to interact with human serum albumin (HSA) and Calf Thymus (ct) DNA, and to inhibit acetylcholinesterase (AChE). We performed BBB permeability and efflux mechanisms studies by means of the in vitro parallel artificial membrane permeability assay (PAMPA-BBB) and several in silico methods, while fluorescence, UV–visible, and circular dichroism spectroscopies were used to determine their ability to interact with HSA and ctDNA. Our results show that all five ionophoric polyphenols can effectively cross the BBB, and can form adducts with both HSA and ctDNA through one binding site and with association constants ranging from 10⁴ to 10⁶ M⁻¹, while still maintaining levels of unbound drug to protein within therapeutic range. Docking and molecular dynamics simulations show that the ionophoric polyphenols preferably bind the hydrophobic cavities of the subdomain IIA of HSA, as many other pharmaceuticals do, with predicted affinities that correlate well with experimental results obtained by spectroscopic techniques. In addition, structurally related compounds 1, 2, and 4 were found to be moderate in vitro AChE inhibitors by interacting with several residues of the active site of the enzyme, as revealed by docking and molecular dynamics simulations. Overall, our results suggest that HSA could be an efficient transport mechanism of the compounds in the bloodstream until reaching the brain, where they could effectively cross the BBB and exert their anti-AD activity, including AChE inhibition. DNA interactions similar to natural resveratrol could in part explain the previously reported nontoxic behavior of the compounds.

阿尔茨海默氏病（AD）是痴呆症的最常见形式，它影响了全球超过4000万人。由于缺乏任何有效的治疗方法，预计发病率将迅速增加。在以前的工作中，我们合成了一家五种离子载体多酚（化合物1 - 5），该有针对性的与AD相关的重要方面，如淀粉样蛋白β肽的毒性聚合，生产活性氧，或Cu的过量存在^{2 +}离子。这里，为了深入了解其潜在的治疗价值，我们已经测试的化合物的能力1 - 5穿过血-脑屏障（BBB），与人血清白蛋白（HSA）和交互小牛胸腺（ct）DNA，并抑制乙酰胆碱酯酶（AChE）。我们通过体外平行人工膜通透性测定法（PAMPA-BBB）和多种计算机方法对BBB的通透性和外流机理进行了研究，同时使用荧光，紫外可见和圆二色性光谱法确定了BBB的相互作用能力HSA和ctDNA。我们的结果表明，所有五个离子载体的多酚都可以有效地穿过血脑屏障，并且可以通过一个结合位点与HSA和ctDNA形成加合物，缔合常数范围为10 ⁴到10 ⁶  M ^-1，同时仍将未结合药物与蛋白质的水平维持在治疗范围内。对接和分子动力学模拟表明，与许多其他药物一样，离子载体多酚优选结合HSA亚结构域IIA的疏水腔，其预测亲和力与通过光谱技术获得的实验结果密切相关。此外，结构相关的化合物1，2，和4如通过对接和分子动力学模拟所揭示，通过与酶活性位点的多个残基相互作用，它们被发现是中等的体外AChE抑制剂。总体而言，我们的结果表明，HSA可能是化合物在血流中直至到达大脑的有效运输机制，在那里它们可以有效地穿过BBB并发挥其抗AD活性，包括抑制AChE。与天然白藜芦醇相似的DNA相互作用可以部分解释先前报道的化合物的无毒行为。