Novel 8-hydroxyquinoline derivatives targeting β-amyloid aggregation, metal chelation and oxidative stress against Alzheimer’s disease

Publication date: 23 July 2018
Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 12
Author(s): Xuelian Yang, Pei Cai, Qiaohong Liu, Jiajia Wu, Yong Yin, Xiaobing Wang, Lingyi Kong
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 Aβ1−42 aggregation and potential antioxidant properties especially compound 5b (IC50 = 5.64 μM for self-induced Aβ 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 Aβ1−42 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.

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