Alzheimer’s disease (AD) is generally recognized as a multifactorial neurodegenerative pathology with an increasing impact on society. Tenuazonic acid (TA) is a natural compound that was recently identified as a potential multitarget ligand with anti-cholinesterase, anti-amyloidogenic and antioxidant activities. Using its structure as a chemical scaffold, we synthesized and evaluated new derivatives (1–5), including tenuazonic-donepezil (TA-DNP) hybrids (4 and 5) due to the clinical importance of the anti-AD drug donepezil. These novel compounds all achieved activity in the micromolar range towards all selected targets and demonstrated to be potentially orally absorbed. Moreover, a selected compound (1) was further investigated as a chelating agent towards copper (II), zinc (II) and iron (III) and showed good chelating ability (pFe = 16.6, pCu = 11.6, pZn = 6.0 at pH 7.4). Therefore, the TA motif can be considered an interesting building block in the search for innovative multi-functional anti-neurodegenerative drugs, as exemplified by hybrid 5, a promising non-cytotoxic lead compound adequate for the early stages of AD, and capable of ameliorating the oxidative status of SH-SY5Y human neuroblastoma cells.

中文翻译：

---

Tenuazonic acid的衍生物作为潜在的新型多靶点抗阿尔茨海默氏病药物

阿尔茨海默氏病（AD）通常被认为是一种多因素神经退行性病变，对社会的影响越来越大。Tenuazonic acid（TA）是一种天然化合物，最近被鉴定为具有抗胆碱酯酶，抗淀粉样蛋白生成和抗氧化活性的潜在多目标配体。使用其结构作为化学支架，由于抗AD药物多奈哌齐的临床重要性，我们合成并评估了新的衍生物（1-5），包括tenuazonic-donepezil（TA-DNP）杂种（4和5）。这些新化合物都在微摩尔范围内对所有选定的靶标实现了活性，并被证明潜在地口服吸收。此外，进一步研究了所选化合物（1）作为对铜（II），锌（II）和铁（III）的螯合剂，并显示出良好的螯合能力（pFe = 16.6，在pH 7.4时pCu = 11.6，pZn = 6.0）。因此，在研究创新的多功能抗神经退行性药物中，TA基序可以被认为是一个有趣的组成部分，例如杂种5，这是一种有前途的无细胞毒性的先导化合物，适合于AD的早期阶段，并能够改善SH-SY5Y人神经母细胞瘤细胞的氧化状态。