Cited by 105Alzheimer's disease research and treatmentsCholinesterase and Neurodegenerative DiseasesSynthesis and biological activity

Design, Synthesis, and Evaluation of Orally Bioavailable Quinoline–Indole Derivatives as Innovative Multitarget-Directed Ligands: Promotion of Cell Proliferation in the Adult Murine Hippocampus for the Treatment of Alzheimer’s Disease

Wang, Zhiren, Hu, Jinhui, Yang, Xiaoping, Feng, Xing, Li, Xingshu, Huang, Ling, Chan, Albert S. C.·2018·Journal of Medicinal Chemistry

Abstract

A novel series of quinoline-indole derivatives were synthesized and evaluated as multitarget-directed ligands for the treatment of Alzheimer's disease (AD). Biological evaluation revealed that the derivatives had multifunctional profiles including antioxidant effects, blood-brain barrier (BBB) penetration, biometal chelation, Aβ aggregation modulation, neurotrophic and neuroprotective properties. Moreover, several representative target derivatives demonstrated hippocampal cell proliferation in living adult mice by intracerebroventricular (icv) injection or oral administration. Further drug-like property analysis demonstrated that the optimized compound, 8d (WI-1758), had liver microsomal metabolic stability, was well tolerated (>2000 mg/kg), and had a rational pharmacokinetic profile, as well as an oral bioavailability of 14.1% and a positive log BB (-0.19) to cross the BBB in vivo. Pharmacodynamics studies demonstrated that chronic oral administration of 8d·HCl substantially ameliorated the cognitive and spatial memory deficits in APP/PS1 AD mice and noticeably reduced overall cerebral β-amyloid deposits.

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Crossref · 10.1021/acs.jmedchem.7b01417

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Authors
Wang, Z., Hu, J., Yang, X., Feng, X., Li, X., Huang, L., & Chan, A. S. C.
Affiliations
  • Sun Yat-sen University (CN)
  • Hunan Normal University (CN)
Corresponding author
  • Li, Xingshu
  • Huang, Ling
Venue
Journal of Medicinal Chemistry
Published
2018-02-08
Volume
61
Issue
5
Pages
1871-1894
ISSN
  • 0022-2623 (ISSN-L)
  • 1520-4804
OpenAlex
W2786700855
Cited by
91
References
49
Citations by year
2026: 5 · 2025: 7 · 2024: 7 · 2023: 12 · 2022: 12 · 2021: 11 · 2020: 19 · 2019: 13 · 2018: 5
FWCI
9.49
Type
journal article
Language
en
Open access
closed
Locations
  • Journal of Medicinal Chemistry (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Ministry of Education of the People's Republic of China (15ykpy04)
  • National Natural Science Foundation of China (21302235, 21772241)
  • Natural Science Foundation of Guangdong Province (2014A030313124)
  • Guangzhou Municipality (201610010111)
  • Government Province (2015TQ01R244)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
  • Physical Sciences › Chemistry › Organic Chemistry › Synthesis and biological activity
Keywords
multi-target-directed ligands, Alzheimer's disease, oral bioavailability, blood-brain barrier penetration, amyloid-beta aggregation, antioxidant activity, neuroprotection, neurotrophic activity, hippocampal cell proliferation, cognitive impairment, spatial memory, APP/PS1 mice, drug-likeness, pharmacokinetics, pharmacodynamics
MeSH terms
Alzheimer Disease, Animals, Blood-Brain Barrier, Hippocampus, Humans, Indoles, Ligands, Memory Disorders, Quinolines, Drug Design, Amyloid beta-Peptides, Cell Proliferation, Mice

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