2. Academic Validation
  3. Novel inhibitors of AChE and Aβ aggregation with neuroprotective properties as lead compounds for the treatment of Alzheimer's disease

Novel inhibitors of AChE and Aβ aggregation with neuroprotective properties as lead compounds for the treatment of Alzheimer's disease

  • Eur J Med Chem. 2022 May 5;235:114305. doi: 10.1016/j.ejmech.2022.114305.
Yulin Liu 1,  Giuseppe Uras 2,  Itse Onuwaje 3,  Wenlong Li 4,  Hong Yao 4,  Shengtao Xu 4,  Xinuo Li 4,  Xinnan Li 4,  James Phillips 3,  Stephanie Allen 5,  Qi Gong 6,  Haiyan Zhang 6,  Zheying Zhu 7,  Jie Liu 8,  Jinyi Xu 9
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, PR China; Department of Organic Chemistry, China Pharmaceutical University, Nanjing, PR China.
  • 2 Division of Molecular Therapeutics and Formulation, School of Pharmacy, The University of Nottingham, University Park, NG7 2RD, United Kingdom; Department of Clinical and Movement Neurosciences, Queen Square Institute of Neurology, University College London, London, United Kingdom.
  • 3 Department of Pharmacology, School of Pharmacy, University College London, London, United Kingdom.
  • 4 State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, PR China.
  • 5 Division of Molecular Therapeutics and Formulation, School of Pharmacy, The University of Nottingham, University Park, NG7 2RD, United Kingdom.
  • 6 CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, PR China.
  • 7 Division of Molecular Therapeutics and Formulation, School of Pharmacy, The University of Nottingham, University Park, NG7 2RD, United Kingdom. Electronic address: [email protected].
  • 8 Department of Organic Chemistry, China Pharmaceutical University, Nanjing, PR China. Electronic address: [email protected].
  • 9 State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, PR China. Electronic address: [email protected].
PMID: 35339839 DOI: 10.1016/j.ejmech.2022.114305
Abstract

A series of sulfone analogs of donepezil were designed and synthesized as novel acetylcholinesterase (AChE) inhibitors with the potent inhibiting Aβ aggregation and providing neuroprotective effects as potential modalities for Alzheimer's disease (AD). Most of the target compounds displayed effective inhibition of AChE, especially compound 24r which displayed powerful inhibitory activity (IC50 = 2.4 nM). Kinetic and docking studies indicated that compound 24r was a mixed-type inhibitor. Furthermore, in glyceraldehyde (GA)-exposed SH-SY5Y differentiated neuronal cells, compound 24r could potently inhibit AChE, reduce tau phosphorylation at S396 residue, provide neuroprotection by rescuing neuronal morphology and increasing cell viability. It was also found to reduce amyloid aggregation in the presence of AChE. In addition, compound 24r showed evident protections from mitochondrial membrane dysfunction and oxidative stress in okadaic acid-induced pharmacological models. Moreover, compound 24r exhibited more effective treatment prospects in vivo than donepezil, including a moderate blood-brain barrier permeability, a more potent AChE inhibitory activity and behavioral improvement in scopolamine-induced cognition-impaired mice model at a much lower dose. Collectively, compound 24r is a promising lead compound for further investigation to discovery and development of new anti-AD agents.

Keywords

AChE inhibitor; Alzheimer's disease; Donepezil; Inhibiting Aβ aggregation; Neuroprotection; Sulfone group.

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