Yang_2018_Bioorg.Med.Chem_26_3191

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 Abeta(1-42) aggregation and potential antioxidant properties especially compound 5b (IC(50) = 5.64 microM for self-induced Abeta aggregation; the oxygen radical absorbance capacity using fluorescein (ORAC-FL) value is 2.63 Trolox equivalents). Notably, 5b can chelate biometals and inhibit Cu(2+)/Zn(2+)-induced Abeta(1-42) aggregation. The cell assays showed that 5b had excellent protective effects against oxidative toxin H(2)O(2) 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.