The production and accumulation of toxic amyloid plaques is one of the hallmarks of Alzheimer’s disease (AD). Amyloid beta (Aβ) peptides undergo self-aggregation to form soluble oligomers, protofibrils and insoluble fibrils. This process is termed as amyloidogenesis and is a major contributor to the observed neuronal damage and memory impairment in the AD brain. Therefore, modulation of Aβ aggregation process is considered to be an effective target to prevent neuronal damage under AD conditions. Modulation of amyloidogenesis involves inhibition of aggregation to form a toxic species or acceleration to drive the aggregation process to form species that are nontoxic by employing well-designed external ligands. In this context, we report a set of 2,3-dihydrophthalazine-1,4-dione (dihydrophthalazinedione, Phz) based small molecules (Phz 1–4) to modulate the Aβ42 aggregation and in cellular toxicity. Our detailed study (thioflavin T fluorescence assay, dot blot and transmission electron microscopy analysis) revealed fluorine containing Phz 4 as the potent modulator of Aβ42 aggregation by accelerating the process to form nontoxic aggregated species through hydrophobic and halogen interactions. Aβ42 aggregates formed in the presence of Phz 4 are mostly nontoxic when compared to the normal amyloid aggregates in the cellular milieu (PC12 cells). This study established that the hydrophobic and halogen interactions can be employed to develop anti-AD drug candidates. The excellent cell viability, effective modulation of Aβ42 aggregation to form nontoxic species and cellular (neuronal) rescue by Phz 4 offer a novel platform to develop therapeutic strategies for AD.

中文翻译：

---

二氢酞嗪二酮类加速淀粉样蛋白 β 肽聚集成无毒物质

毒性淀粉样蛋白斑块的产生和积累是阿尔茨海默病 (AD) 的标志之一。淀粉样蛋白 β (Aβ) 肽经历自聚集形成可溶性寡聚体、原纤维和不溶性原纤维。这个过程被称为淀粉样蛋白生成并且是在 AD 大脑中观察到的神经元损伤和记忆障碍的主要促成因素。因此，Aβ 聚集过程的调节被认为是预防 AD 条件下神经元损伤的有效靶点。淀粉样蛋白生成的调节涉及抑制聚集形成有毒物质，或通过使用精心设计的外部配体加速聚集过程以形成无毒物质。在这种情况下，我们报告了一组 2,3-dihydrophthalazine-1,4-dione (dihydrophthalazinedione, Phz) 基于小分子 (Phz 1-4) 以调节 Aβ42 聚集和细胞毒性。我们的详细研究（硫代黄素 T 荧光测定、斑点印迹和透射电子显微镜分析）揭示了含氟的 Phz 4 作为 Aβ42 聚集的有效调节剂，通过疏水和卤素相互作用加速形成无毒聚集物质的过程。与细胞环境（PC12 细胞）中的正常淀粉样蛋白聚集体相比，在 Phz 4 存在下形成的 Aβ42 聚集体大多是无毒的。该研究确定疏水和卤素相互作用可用于开发抗 AD 候选药物。出色的细胞活力，