Amyloid-β peptides (Aβ) fibrillation is the hallmark of Alzheimer's disease (AD). However, it has been challenging to discover potent agents in order to inhibit Aβ fibrillation. Herein, we demonstrated the effect of resorcinarene on inhibiting Aβ fibrillation in vitro via experimental and computational methods. Aβ were incubated with different concentrations of resorcinarene so as to monitor the kinetics by using thioflavin T binding assay. The results, which were further confirmed by far-UV CD spectroscopy and atomic force microscopy, strongly indicated that the higher concentration of resorcinarene, the more effective the inhibition of Aβ fibrillation. A cytotoxicity study showed that when sea urchin embryos were exposed to the resorcinarene, the majority survived due to the resorcinarene low toxicity. In addition, when the resorcinarene was added, the formation of toxic Aβ 42 species was delayed. Computational studies of Aβ fibrillation, including docking simulations and MD simulations, illustrated that the interaction between inhibitor resorcinarene and Aβ is driven by the non-polar interactions. These studies display a novel strategy for the exploration of promising antiamyloiddogenic agents for AD treatments.

Two sulfonated resorcinarenes were synthesized by reacting C-tetra(butyl) resorcinarene or C-tetra(2-(methylthio)ethyl)resorcinarene with formaldehyde in the presence of sodium sulfite. Their structures were determined via FT-IR, ¹H-NMR, ¹³C-NMR and mass spectrometry. Thermal gravimetric analyses of the derivatives were also carried out and revealed the presence of water molecules in the solid state. The sulfonated product of C-tetra(butyl)resorcinarene was characterized by an X-ray crystal structure determination. The asymmetric unit contains eight molecules of water and two of acetone, and analysis indicated that sulfonated resorcinarene prefers a cone configuration (rccc conformation) in the solid state. In the crystal array, classical hydrogen bond interactions O-H···O and intermolecular contacts were observed. In the crystal packing, a linear array of capsules of sulfonated resorcinarenes was generated for a chain of sodium atoms and sulfonate groups.