1. Academic Validation
  2. Dual GSK-3β/AChE Inhibitors as a New Strategy for Multitargeting Anti-Alzheimer's Disease Drug Discovery

Dual GSK-3β/AChE Inhibitors as a New Strategy for Multitargeting Anti-Alzheimer's Disease Drug Discovery

  • ACS Med Chem Lett. 2018 Feb 9;9(3):171-176. doi: 10.1021/acsmedchemlett.7b00463.
Xue-Yang Jiang 1 Ting-Kai Chen 1 Jun-Ting Zhou 1 Si-Yu He 1 Hong-Yu Yang 1 Yao Chen 2 Wei Qu 1 Feng Feng 1 Hao-Peng Sun 1
Affiliations

Affiliations

  • 1 Department of Natural Medicinal Chemistry and Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.
  • 2 School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
Abstract

Designing multitarget-directed ligands (MTDLs) is considered to be a promising approach to address complex and multifactorial maladies such as Alzheimer's disease (AD). The concurrent inhibition of the two crucial AD targets, glycogen synthase kinase-3β (GSK-3β) and human acetylcholinesterase (hAChE), might represent a breakthrough in the quest for clinical efficacy. Thus, a novel family of GSK-3β/AChE dual-target inhibitors was designed and synthesized. Among these hybrids, 2f showed the most promising profile as a nanomolar inhibitor on both hAChE (IC50 = 6.5 nM) and hGSK-3β kinase activity (IC50 = 66 nM). It also showed good inhibitory effect on β-amyloid self-aggregation (inhibitory rate = 46%) at 20 μM. Western blot analysis revealed that compound 2f inhibited hyperphosphorylation of Tau Protein in mouse neuroblastoma N2a-Tau cells. In vivo studies confirmed that 2f significantly ameliorated the cognitive disorders in scopolamine-treated ICR mice and less hepatotoxicity than tacrine. This study provides new leads for assessment of GSK-3β and AChE pathway dual inhibition as a promising strategy for AD treatment.

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