Synthesis and evaluation of tetrahydroisoquinoline-benzimidazole hybrids as multifunctional agents for the treatment of Alzheimer's disease.


Research Center for Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, People's Republic of China. Electronic address: [Email]


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 (IC50 = 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.


Alzheimer's disease,Anti-neuroinflammation,BACE1 inhibition,Neuroprotection,Tetrahydroisoquinoline-benzimidazole hybrids,

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