Structural Optimization and Biological Evaluation of Substituted Bisphenol A Derivatives as β-Amyloid Peptide Aggregation Inhibitors

Yu Zhou, Chunyi Jiang, Yaping Zhang, Zhongjie Liang, Wenfeng Liu, Liefeng Wang, Cheng Luo, Tingting Zhong, Yi Sun, Linxiang Zhao, Xin Xie, Hualiang Jiang, Naiming Zhou, Dongxiang Liu and Hong Liu

The aggregation of Aβ is a crucial step in the etiology of Alzheimer's disease. Our previous work showed
that Aβ undergoes R-helix/β-sheet intermediate structures during the conformational transition, and an
Aβ aggregation inhibitor (1) was discovered by targeting the intermediates. Here, structure optimization
toward compound 1 was performed and 34 novel derivatives were designed and synthesized. Nine
compounds showedmore effective inhibitory activity than the hit compound 1 in ThT fluorescence assay.
Among them, compound 43 demonstratedmore excellent inhibitory potency,which not only can suppress
the aggregation of Aβ but also can dissolve the preformed fibrils as shown by CD spectroscopy, PICUP
and AFM assays. Cellular assay indicated that 43 has no toxicity to neuronal cells, moreover, can
effectively inhibit Aβ1-42-induced neutrotoxicity and increase the cell viability. Together, on the basis of
these positive results, these novel chemical structures may provide a promising potential for therapeutic
applications in AD and other types of neurodegenerative disorders.