Department of Pharmacy and Biotechnology, Alma Mater Studiorum - University of Bologna, 40126 Bologna, Italy.
Department of Chemistry in Pharmaceutical Sciences, Organic and Medicinal Chemistry Unit, Faculty of Pharmacy, Universidad Complutense, 28040 Madrid, Spain.
Bioorg Med Chem. 2023 Aug 15;91:117419. doi: 10.1016/j.bmc.2023.117419. Epub 2023 Jul 19.
Multi-target drug discovery is one of the most active fields in the search for new drugs against Alzheimer's disease (AD). This is because the complexity of AD pathological network might be adequately tackled by multi-target-directed ligands (MTDLs) aimed at modulating simultaneously multiple targets of such a network. In a continuation of our efforts to develop MTDLs for AD, we have been focusing on the molecular hybridization of the acetylcholinesterase inhibitor tacrine with the aim of expanding its anti-AD profile. Herein, we manipulated the structure of a previously developed tacrine-quinone hybrid (1). We designed and synthesized a novel set of MTDLs (2-6) by replacing the naphthoquinone scaffold of 1 with that of 2,5,8-quinolinetrione. The most interesting hybrid 3 inhibited cholinesterase enzymes at nanomolar concentrations. In addition, 3 exerted antioxidant effects in menadione-induced oxidative stress of SH-SY5Y cells. Importantly, 3 also showed low hepatotoxicity and good anti-amyloid aggregation properties. Remarkably, we uncovered the potential of the quinolinetrione scaffold, as a novel anti-amyloid aggregation and antioxidant motif to be used in further anti-AD MTDL drug discovery endeavors.
多靶点药物发现是寻找阿尔茨海默病（AD）新药最活跃的领域之一。这是因为多靶点导向配体（MTDL）可以同时调节 AD 网络的多个靶点，从而可以充分解决 AD 病理网络的复杂性。在我们继续努力开发用于 AD 的 MTDL 的过程中，我们一直专注于乙酰胆碱酯酶抑制剂他克林与旨在扩大其抗 AD 谱的目标的分子杂交。在此，我们操纵了先前开发的他克林-醌杂合体（1）的结构。我们通过用 2,5,8-喹啉三酮代替 1 的萘醌支架设计并合成了一组新型 MTDL（2-6）。最有趣的杂种 3 以纳摩尔浓度抑制胆碱酯酶。此外，3 在 MENADIONE 诱导的 SH-SY5Y 细胞氧化应激中发挥抗氧化作用。重要的是，3 还表现出低肝毒性和良好的抗淀粉样蛋白聚集特性。值得注意的是，我们揭示了喹啉三酮支架的潜力，作为一种新型的抗淀粉样蛋白聚集和抗氧化基序，可用于进一步的抗 AD MTDL 药物发现工作。
