Pharmaceutical Chemistry, School of Pharmacy, University of the Western Cape, Bellville, South Africa.
J Enzyme Inhib Med Chem. 2020 Dec;35(1):1596-1605. doi: 10.1080/14756366.2020.1801673.
A series of multi-target directed edaravone derivatives bearing -benzyl pyridinium moieties were designed and synthesised. Edaravone is a potent antioxidant with significant neuroprotective effects and -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--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 AChE inhibitory activities were observed for selected compounds (IC: 1.2-4.6 µM) with limited butyrylcholinesterase inhibitory activity (IC's >160 µM), indicating excellent selectivity towards AChE (SI: 46 - >278). The compounds also showed considerable antioxidant ability, similar to edaravone. studies indicated that these compounds should cross the blood-brain barrier, making them promising lead molecules in the development of anti-Alzheimer's agents.
一系列带有 -苄基吡啶鎓部分的多靶点定向依达拉奉衍生物被设计和合成。依达拉奉是一种有效的抗氧化剂，具有显著的神经保护作用，-苄基吡啶鎓先前作为双位点结合的一部分，表现出积极的结果，外周阴离子部位 (PAS) 和催化阴离子部位 (CAS)，乙酰胆碱酯酶 (AChE) 抑制剂。设计的依达拉奉-苄基吡啶鎓杂合化合物在 AChE 活性部位对接。结果表明与保守氨基酸 (PAS 中的色氨酸 279 和 CAS 中的色氨酸 84) 相互作用，表明具有良好的双位点抑制活性。选定的化合物表现出显著的 AChE 抑制活性 (IC：1.2-4.6 μM)，对丁酰胆碱酯酶的抑制活性有限 (IC's >160 μM)，表明对 AChE 具有极好的选择性 (SI：46- >278)。这些化合物还表现出相当强的抗氧化能力，类似于依达拉奉。研究表明，这些化合物应该能够穿过血脑屏障，使它们成为开发抗阿尔茨海默病药物的有前途的先导分子。
