LAQV-REQUIMTE, University of Évora, Institute for Research and Advanced Studies, Rua Romão Ramalho, 59, 7000 Évora, Portugal.
Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, Apartado 1203, E-41071 Seville, Spain.
Bioorg Chem. 2020 May;98:103753. doi: 10.1016/j.bioorg.2020.103753. Epub 2020 Mar 19.
Our goal was the evaluation of a series of N-1,2,3-triazole-isatin derivatives for multi-target activity which included cholinesterase (ChE) inhibition and β-amyloid (Aβ) peptide anti-aggregation. The compounds have shown considerable promise as butyrylcholinesterase (BuChE) inhibitors. Although the inhibition of eel acetylcholinesterase (eeAChE) was weak, the inhibitions against equine BuChE (eqBuChE) and human BuChE (hBuChE) were more significant with a best inhibition against eqBuChE of 0.46 μM. In some cases, these molecules gave better inhibitions for hBuChE than eqBuChE. For greater insights into their mode of action, molecular docking studies were carried out, followed by STD-NMR validation. In addition, some of these compounds showed weak Aβ anti-aggregation activity. Hepatotoxicity studies showed that they were non-hepatoxic and neurotoxicity studies using neurite outgrowth experiments led to the conclusion that these compounds are only weakly neurotoxic.
我们的目标是评估一系列 N-1,2,3-三唑-色胺衍生物的多靶点活性，包括胆碱酯酶（ChE）抑制和β-淀粉样肽（Aβ）肽抗聚集。这些化合物已显示出作为丁酰胆碱酯酶（BuChE）抑制剂的巨大潜力。虽然对鳗鱼乙酰胆碱酯酶（eeAChE）的抑制作用较弱，但对马源 BuChE（eqBuChE）和人源 BuChE（hBuChE）的抑制作用更为显著，对 eqBuChE 的最佳抑制作用为 0.46 μM。在某些情况下，这些分子对 hBuChE 的抑制作用优于 eqBuChE。为了更深入地了解它们的作用模式，进行了分子对接研究，并进行了 STD-NMR 验证。此外，这些化合物中的一些显示出较弱的 Aβ 抗聚集活性。肝毒性研究表明它们无肝毒性，神经毒性研究通过神经突生长实验得出结论，这些化合物仅具有较弱的神经毒性。
