Design, Sythesis And Bioassay Of Compounds As β-Amyloid Peptide Aggregation Inhibitor

Alzheimer's disease(AD)is a progressive neurodegenerative disease that is characterized pathologically by the deposition ofβ-amyloid(Aβ)-containmg extracellular senile plaques,intracellular neurofibrillary tangles and neuronal loss.Until now,there is no effective treatment for AD.Although the etiology of Alzheimer's disease is not fully understood,compelling evidence indicates that deposition of aggregates composed by the amyloid beta peptide(Aβ)is the central event in the disease pathogenesis.Therefore,an attractive therapeutic strategy is to prevent or reverse Aβaggregation.In this paper,the procedures of discovering and forming Aβ,mechanisms of action in AD induced by Aβ,development of theβ-amyloid peptide as a therapeutic target and the procedures of discovering lead compound DC-AB1(α,α'-[(1-Methylethylidene)bis[(2,6-dibromo-4, 1-phenylene)oxymethylene]]bis-4-morpholineethanol)were summarized.Thirty-two target compounds(A1-A32)were designed and synthesized as DC-AB1 a lead compound.Their structures were confirmed by ¹H NMR,¹³C NMR and MS.Using thioflavin T(ThT)fluorescence assay,the anti-Aβaggregative activity of the target compounds was tested.Twenty-four target compounds presented inhibitory activities, nine target compounds showed better inhibitory activity than DC-AB1.The anti-Aβaggregative activity of the most potent compound(A12,α,α'-[(1-Methylethylidene)bis [(2,6-dimethyl-4,1-phenylene)oxymethylene]]bis[4-(phenylmethyl)-1-piperazineethanol],IC₅₀ =91.56μM)was about 12 times as that of DC-AB1(IC₅₀=1100μM).The structures and anti-Aβaggregative activity relationships of target compounds were surveyed.