Synthesis and Evaluation of New Cyclodextrin Derivatives as Amyloid‐β Aggregation Inhibitors

The presence of extracellular amyloid‐beta (Aβ) plaques is one of the pathological hallmarks of Alzheimer's disease. Appropriately functionalized compounds can modulate amyloidogenesis. Here, we report a new class of cyclodextrin (CyD) derivatives rationally designed to improve the Aβ recognition and to modulate its aggregation. In particular, a dimethylamino aromatic moiety was conjugated to βCyD or γCyD to explore how different structural aspects of these derivatives could influence the recognition and the aggregation of Aβ. The conjugation of the Aβ recognition moiety to CyDs resulted in a significant suppression of the self‐assembly propensity of Aβ when the dimethylamino aromatic moiety was attached to the upper rim of βCyD. The activity of the derivatives toward Aβ confirms that the conjugation of CyDs with Aβ recognition moieties may be considered a promising approach for designing new molecules that interfere with Aβ aggregation. The conjugation of an Aβ recognition moiety to different cyclodextrins resulted in a significant suppression of the self‐assembly propensity of Aβ peptide. In particular, when the dimethylamino aromatic moiety was attached to the upper rim of β‐cyclodextrin, the obtained compound was more active in inhibiting Aβ aggregation as demonstrated by different techniques.