Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
Stem Cells Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
Chem Biodivers. 2022 Jan;19(1):e202100599. doi: 10.1002/cbdv.202100599. Epub 2021 Dec 6.
A new series of imino-2H-chromene derivatives were rationally designed and synthesized as novel multifunctional agents against Alzheimer's disease. A set of phenylimino-2H-chromenes as well as the newly synthesized iminochromene derivatives were evaluated as BACE1, acetylcholinesterase (AChE), and butyrylcholinesterase (BuChE) inhibitors. The results indicated that among the iminochromene set, 10c bearing fluorobenzyl moiety was the most potent BACE1 inhibitor with an IC value 6.31 μM. In vitro anti-cholinergic activities demonstrated that compound 10a bearing benzyl pendant was the best inhibitor of AChE (% inhibition at 30 μM=24.4) and BuChE (IC =3.3 μM). Kinetic analysis of compound 10a against BuChE was also performed and showed a mixed-type inhibition pattern. The neuroprotective assessment revealed that compound 11b, a phenylimino-2H-chromene derivative with hydroxyethyl moiety, provided 32.3 % protection at 25 μM against Aβ-induced PC12 neuronal cell damage. In addition, docking and simulation studies of the most potent compounds against BACE1 and BuChE confirmed the experimental results.
一系列新型的亚氨基-2H-色烯衍生物被合理设计并合成，作为治疗阿尔茨海默病的新型多功能药物。一组苯基亚氨基-2H-色烯以及新合成的亚氨基色烯衍生物被评估为 BACE1、乙酰胆碱酯酶 (AChE) 和丁酰胆碱酯酶 (BuChE) 的抑制剂。结果表明，在亚氨基色烯组中，带有氟苄基部分的 10c 是最有效的 BACE1 抑制剂，IC 值为 6.31 μM。体外抗胆碱能活性表明，带有苄基侧链的化合物 10a 是 AChE（在 30 μM 时抑制率为 24.4%）和 BuChE（IC =3.3 μM）的最佳抑制剂。还对化合物 10a 对 BuChE 的动力学分析进行了研究，结果表明其为混合型抑制模式。神经保护评估表明，具有羟乙基部分的苯基亚氨基-2H-色烯衍生物 11b 在 25 μM 时对 Aβ 诱导的 PC12 神经元细胞损伤提供了 32.3%的保护。此外，针对 BACE1 和 BuChE 的最有效化合物的对接和模拟研究证实了实验结果。
