Synthesis And Biological Evaluation Of Deferiprone-resveratrol Hybrids As Agents For Alzheimer’s Disease

ObjectivesAlzheimer’s disease(AD)is a modern health killer of the elder.The pathogenesis of AD is complexed and not fully understood.Studies have shown that many factors such as the accumulation of amyloid metal ions(iron,copper,zinc)in the brain accelerates the pathogenesis of AD.On the basis of the facts that the resveratrol could counteract Aβ toxicity by its antioxidant properties and that 3-hydroxypyridin-4-one possesses a potent chelation activity for iron,a series of 3-hydroxypyridine-4-one—resveratrol hybrids 3a-3k,4a-4k,8a-8k have been synthesized and evaluated as antioxidants,metal-chelating agents as well as inhibitors of both self-induced and metal-induced Aβ1-42 plaque formation for the treatment of Alzheimer’s disease(AD).MethodsThis study mainly includes:1.Synthesis of deferiprone-resveratrol hybrids by using chemical method.2.To determine the antioxidant capacity of compounds using ABTS method.3.The affinity constants and chelating ratios of the compounds to ferric ions were determined by fluorescence and UV-spectroscopies respectively.4.ThT method was used to determine the inhibition and disaggrement of Aβ1-42.Results1.33 deferiprone-resveratrol hybrids were successfully synthesized and the structures were verified by nuclear magnetic resonance.2.Most of the compounds had higher antioxidant capacity than the control trolox.3.The affinity constants of 22 pyridinone-resveratrol hybrids to trivalent iron ion are about 20,and the pyrone-resveratrol hybrids also favor ferric ion.The compounds were completely chelated in the presence of 0.25 eq iron ion.4.The screening results showed that half of the molecules exhibited a good ability to inhibit self-induced Aβ1-42 aggregation.Especially 3i(IC50(ABTS)=1.73μM)IC50(Aβ1-42)=10.7μM)and 4f(IC50(ABTS)=4.02μM,IC50(Aβ1-42)=2.94 μM),8i(IC50(ABTS)=1.94μM,IC50(Aβ1-42)=7.20μM)and 8j(IC50(ABTS)=1.18μMIC50(Aβ1-42)=15.29μM),were considered as excellent antioxidants and self-induced Aβ1-42 aggregation inhibitors.Furthermore,it is capable of inhibiting Fe3+ and Cu2+-induced AP1-42 aggregation and the order of metal ions that the four compounds inhibit their induced Aβ1-42 aggregation is Fe3+>Cu2+.ConclusionAll of the data suggested that 3i and 4f,8i and 8j are excellent multifunctional anti-AD compounds with high antioxidant activity,good inhibition of self-induced amyloid aggregation,and they can also effectively chelate metal and inhibit metal-induced amyloid beta aggregation.The further studies on the deferiprone-resveratrol hybrids are currently in process.