Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 26, Issue 12, Pages 3191-3201Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2018.04.043
Keywords
8-Hydroxyquinoline; beta-Amyloid; Neuroprotection; Antioxidant; Alzheimer's disease
Funding
- National Natural Science Foundation of China [81573313, 81602985]
- Qing Lan Project of Jiangsu Province in China
- Innovative Research Team in University [IRT_15R63]
- Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD)
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A series of multitargeted 8-hydroxyquinoline derivatives were designed and synthesized for the treatment of Alzheimer's disease (AD). In vitro studies indicated that most of the prepared compounds exhibited significant inhibitory effects against self-induced A beta(1-42) aggregation and potential antioxidant properties especially compound 5b (IC50 = 5.64 lM for self-induced Ab aggregation; the oxygen radical absorbance capacity using fluorescein (ORAC-FL) value is 2.63 Trolox equivalents). Notably, 5b can chelate biometals and inhibit Cu2+/Zn2+-induced A beta(1-42) aggregation. The cell assays showed that 5b had excellent protective effects against oxidative toxin H2O2 and presented low neurotoxicity in PC12 cells. Furthermore, 5b could penetrate the blood-brain barrier (BBB) in vitro and did not show any acute toxicity in mice at doses up to 2000 mg/kg in vivo. Our findings provide a rationale for the potential application of compound 5b as a lead compound in AD therapy. (C) 2018 Elsevier Ltd. All rights reserved.
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