Department of Clinical and Diagnostic Science, University of Alabama at Birmingham, Birmingham, Alabama, USA.
Department of Discovery and Biomedical Sciences, University of South Carolina, Columbia, South Carolina, USA.
Drug Dev Res. 2023 Jun;84(4):671-680. doi: 10.1002/ddr.21708. Epub 2020 Jun 16.
Current therapeutic drugs for Alzheimer's disease (AD) can only offer limited symptomatic benefits and do not halt disease progression. Multitargeted directed ligands (MTDLs) have been considered to be a feasible way to treat AD due to the multiple neuropathological processes in AD. Previous studies proposed that compounds containing two aromatic groups connected by a carbon chain should act as effective amyloid β (Aβ) aggregation inhibitors although the optimal length of the carbon chain has not been explored. In the current study, a series of naphthalimide analogs were designed and synthesized based on the proposed structure and multiple bioactivities beneficial to the AD treatment were reported. In vitro studies showed that compound 8, which has two aromatic groups connected by a two-carbon chain, exhibited significant inhibition of Aβ aggregation through the prevention of elongation and association of Aβ fibril growth. Furthermore, this compound also displayed antioxidative activities and neuroprotection from Aβ monomer induced toxicity in primary cortical neurons. The results of the present study highlight a novel naphthalimide-based compound 8 as a promising MTDL against AD. Its structural elements can be further explored for enhanced therapeutic capabilities.
目前用于治疗阿尔茨海默病（AD）的药物只能提供有限的对症治疗效果，无法阻止疾病的进展。由于 AD 存在多种神经病理学过程，多靶点导向配体（MTDL）被认为是治疗 AD 的一种可行方法。先前的研究提出，含有两个通过碳链连接的芳基基团的化合物应该可以作为有效的淀粉样蛋白β（Aβ）聚集抑制剂，尽管尚未探索最佳碳链长度。在本研究中，基于提出的结构和对 AD 治疗有益的多种生物活性，设计并合成了一系列萘酰亚胺类似物。体外研究表明，化合物 8 通过阻止 Aβ 纤维生长的延伸和聚集，对 Aβ 聚集表现出显著的抑制作用，化合物 8 含有两个通过两个碳链连接的芳基基团。此外，该化合物还显示出抗氧化活性和对原代皮质神经元中 Aβ 单体诱导毒性的神经保护作用。本研究结果强调了一种新型基于萘酰亚胺的化合物 8 作为一种有前途的 AD 多靶点治疗药物。可以进一步探索其结构元素以增强治疗能力。
