Research Center for Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, People's Republic of China.
Research Center for Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, People's Republic of China.
Eur J Med Chem. 2019 Apr 1;167:133-145. doi: 10.1016/j.ejmech.2019.02.008. Epub 2019 Feb 4.
A novel series of tetrahydroisoquinoline-benzimidazole hybrids have been designed and synthesized as multifunctional agents against Alzheimer's disease (AD). These compounds were evaluated for their inhibition of neuroinflammation and human β-secretase (hBACE1), and neuroprotective activity. Among them, compound BD3 possessed significant anti-neuroinflammatory activity (IC = 5.07 μM against nitric oxide production) through inhibiting the expression and secretion of proinflammatory cytokines in BV2 cells. Compound BD3 also exhibited moderate hBACE1 inhibitory activity (65.7% inhibition at 20 μM) and potent neuroprotective effect by increasing GSH level and reducing ROS production (91.8% cell viability at 5 μM). Parallel artificial membrane permeation assay demonstrated that BD3 could cross the blood-brain barrier (BBB). Thus, this study demonstrates that the compounds with tetrahydroisoquinoline-benzimidazole scaffold are potential anti-AD agents, and they are worth for the further development.
我们设计并合成了一系列新型的四氢异喹啉-苯并咪唑杂合体，作为治疗阿尔茨海默病（AD）的多效药物。评估了这些化合物对神经炎症和人β-分泌酶（hBACE1）的抑制作用，以及神经保护活性。其中，化合物 BD3 通过抑制 BV2 细胞中促炎细胞因子的表达和分泌，表现出显著的抗炎活性（对一氧化氮生成的抑制率为 5.07 μM）。BD3 还具有适度的 hBACE1 抑制活性（20 μM 时抑制率为 65.7%），并通过增加 GSH 水平和减少 ROS 产生（在 5 μM 时细胞活力为 91.8%）表现出强大的神经保护作用。平行人工膜渗透测定表明，BD3 可以穿透血脑屏障（BBB）。因此，这项研究表明，具有四氢异喹啉-苯并咪唑骨架的化合物是有潜力的抗 AD 药物，值得进一步开发。
