Repurposing nitrocatechols: 5-Nitro-α-cyanocarboxamide derivatives of caffeic acid and caffeic acid phenethyl ester effectively inhibit aggregation of tau-derived hexapeptide AcPHF6

Eur J Med Chem. 2019 Apr 1;167:146-152. doi: 10.1016/j.ejmech.2019.02.006. Epub 2019 Feb 4.

Abstract

Polyphenols like caffeic acid and its phenethyl ester have been associated with potent anti-aggregating activity. Accordingly, we screened a library of polyphenols and synthetic derivatives thereof for their capacity to inhibit tau-aggregation using a thioflavin T-based fluorescence method. Our results show that the nitrocatechol scaffold is required for a significant anti-aggregating activity, which is enhanced by introducing bulky substituents at the side chain. A remarkable increase in activity was observed for α-cyanocarboxamide derivatives 26-27. Molecular docking studies showed that the amide bond provides superior conformational stability in the steric zipper assembly of tau, which drives the increase in activity. We also found that derivatives 24-27 were potent chelators of copper(II) - a property of pharmacological significance in abnormal protein aggregation. These small molecules can provide promising leads to develop new drugs for tauopathies and AD. These findings open a new window on the repurposing of nitrocatechols beyond their established role as catechol-O-methyltransferase inhibitors.

Keywords: Caffeic acid; Caffeic acid phenethyl ester; Metal chelation; Nitrocatechols; Tau aggregation inhibitors.

MeSH terms

  • Caffeic Acids / chemistry*
  • Caffeic Acids / pharmacology
  • Catechols / chemistry*
  • Chelating Agents
  • Copper
  • Drug Design
  • Nitro Compounds / chemistry*
  • Peptides
  • Phenylethyl Alcohol / analogs & derivatives*
  • Phenylethyl Alcohol / pharmacology
  • Polyphenols / chemistry
  • Protein Aggregation, Pathological / drug therapy*
  • Small Molecule Libraries
  • Tauopathies / drug therapy
  • tau Proteins / chemistry

Substances

  • Caffeic Acids
  • Catechols
  • Chelating Agents
  • Nitro Compounds
  • Peptides
  • Polyphenols
  • Small Molecule Libraries
  • nitrocatechol
  • tau Proteins
  • Copper
  • caffeic acid phenethyl ester
  • Phenylethyl Alcohol