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Review | Regular issue | Vol 106, No. 5, 2023, pp.797-818
Published online, 9th February, 2023
DOI: 10.3987/REV-22-999
Design, Synthesis and Evaluation of Catechol-Based Amyloid Beta Aggregation Inhibitors

Hiroyuki Konno* and Kenta Teruya

*Department of Chemistry and Biological Engineering, Graduate School of Science and Engineering, Yamagata University, Yonezawa, Yamagata 992-8510, Japan


The use of small molecules to inhibit amyloid β aggregation is one approach under investigation to prevent the onset of Alzheimer’s disease (AD). One such small molecule is curcumin, but its utility is limited by poor water solubility and hence poor bioavailability. In this review, we summarize the findings of structure-activity relationship studies of curcumin and diaryl γ-dihydropyrone, undertaken to improve their inhibitory effect and physical properties. The key findings are: phenolic hydroxy groups can be introduced at the 2 and 3,4-positions of phenol rings, the C7 spacer of curcumin is essential for good anti-amyloid β aggregation activity; and the catechol moiety is important for both anti-aggregation activity and water solubility. The combination of the C5 spacer unit and mono ketone of curcumin analogues is more effective for water solubility with high anti-amyloid β aggregation activity. Diaryl γ-dihydropyrone with hydroxy groups on phenol rings as cyclocurcumin mimetics also showed anti-amyloid β aggregation activity and high water solubility. Analogues of berberine, a benzylisoquinoline alkaloid also of interest to treat central nervous system diseases, are also reviewed. Finally, we review efforts to develop fluorescent curcumin analogues for use as diagnostic agents.