Tolcapone

The Schiff base derived from the condensation of 4-aminosalicylic acid with 2,3-dihydroxybenzaldehyde was synthesized and characterized by using experimental techniques, theoretical calculations, and in silico methods. Single-crystal X-ray diffraction analysis showed that the compound crystallizes in the triclinic P1̅ space group with two molecules in the asymmetric unit, both adopting a zwitterionic keto form. In silico studies predict high gastrointestinal absorption, low toxicity, and potential activity as a transthyretin (TTR) inhibitor, with binding affinity comparable to that of the drug Tolcapone, suggesting that the synthesized compound may be a promising scaffold for a TTR stabilizer.

Tolcapone, a clinically approved drug for the treatment of Parkinson’s disease as an adjunct therapy, has recently emerged as a potential modulator of amyloid‐β aggregation and toxicity, which are hallmark features of Alzheimer’s disease and are also involved in ocular neurodegenerative disorders, including glaucoma and age‐related macular degeneration. Despite these noteworthy findings, the molecular basis of the interaction between amyloid‐β and tolcapone remains poorly understood, and the mechanisms by which tolcapone affects metal–amyloid‐β species have yet to be explored. In this work, we investigate the binding interactions of tolcapone with both copper‐free amyloid‐β and copper‐associated amyloid‐β complexes, using a combination of techniques including UV–vis spectroscopy, circular dichroism, mass spectrometry, and surface plasmon resonance. The results reveal that tolcapone binds directly to amyloid‐β monomers. Furthermore, in vitro assays confirm the capacity of tolcapone to act as a radical scavenger and to compete with amyloid‐β for the binding of copper ions. Altogether, our findings suggest that tolcapone exerts a multifaceted protective effect, potentially inhibiting toxic metal‐free and metal aggregation pathways by preventing metal coordination to amyloid‐β or disrupting preformed amyloid‐β–metal complexes, thus offering new perspectives to explore and develop its analogs for the treatment of neurodegenerative disorders.