A series of multi-target directed edaravone derivatives bearing N-benzyl pyridinium moieties were designed and synthesised. Edaravone is a potent antioxidant with significant neuroprotective effects and N-benzyl pyridinium has previously exhibited positive results as part of a dual-site binding, peripheral anionic site (PAS) and catalytic anionic site (CAS), acetylcholinesterase (AChE) inhibitor. The designed edaravone-N-benzyl pyridinium hybrid compounds were docked within the AChE active site. The results indicated interactions with conserved amino acids (Trp279 in PAS and Trp84 in CAS), suggesting good dual-site inhibitory activity. Significant in vitro AChE inhibitory activities were observed for selected compounds (IC50: 1.2-4.6 µM) with limited butyrylcholinesterase inhibitory activity (IC50's >160 µM), indicating excellent selectivity towards AChE (SI: 46 - >278). The compounds also showed considerable antioxidant ability, similar to edaravone. In silico studies indicated that these compounds should cross the blood-brain barrier, making them promising lead molecules in the development of anti-Alzheimer's agents.

中文翻译：

---

带有 N-苄基吡啶部分的依达拉奉衍生物作为多功能抗阿尔茨海默病药物的设计、合成和生物学评价。


设计并合成了一系列带有N-苄基吡啶部分的多靶点定向依达拉奉衍生物。依达拉奉是一种有效的抗氧化剂，具有显着的神经保护作用，N-苄​​基吡啶鎓此前作为双位点结合、外周阴离子位点 (PAS) 和催化阴离子位点 (CAS)、乙酰胆碱酯酶 (AChE) 抑制剂的一部分表现出积极的结果。设计的依达拉奉-N-苄基吡啶鎓杂化化合物对接在AChE活性位点内。结果表明与保守氨基酸（PAS 中的 Trp279 和 CAS 中的 Trp84）存在相互作用，表明具有良好的双位点抑制活性。所选化合物具有显着的体外 AChE 抑制活性（IC50：1.2-4.6 µM），但丁酰胆碱酯酶抑制活性有限（IC50 >160 µM），表明对 AChE 具有出色的选择性（SI：46 - >278）。这些化合物还表现出相当大的抗氧化能力，与依达拉奉类似。计算机研究表明，这些化合物应该能够穿过血脑屏障，使其成为抗阿尔茨海默病药物开发中有希望的先导分子。