Resveratrol-Maltol and Resveratrol-Thiophene Hybrids as Cholinesterase Inhibitors and Antioxidants: Synthesis, Biometal Chelating Capability and Crystal Structure

Molecules. 2022 Sep 27;27(19):6379. doi: 10.3390/molecules27196379.

Abstract

New resveratrol-thiophene and resveratrol-maltol hybrids were synthesized as cholinesterase inhibitors and antioxidants. As with photostability experiments, biological tests also found remarkable differences in the properties and behavior of thiophene and maltol hybrids. While resveratrol-thiophene hybrids have excellent inhibitory and antioxidant properties (similar to the activity of reference drug galantamine), maltols have been proven to be weaker inhibitors and antioxidants. The molecular docking of selected active ligands gave insight into the structures of docked enzymes. It enabled the identification of interactions between the ligand and the active site of both cholinesterases. The maltols that proved to be active cholinesterase inhibitors were able to coordinate Fe3+ ion, forming complexes of 1:1 composition. Their formation constants, determined by spectrophotometry, are very similar, lgK = 11.6-12.6, suggesting that Fe3+ binds to the common hydroxy-pyranone moiety and is hardly affected by the other aromatic part of the ligand. Accordingly, the characteristic bands in their individual absorption spectra are uniformly red-shifted relative to those of the free ligands. The crystal structures of two new resveratrol-maltol hybrids were recorded, giving additional information on the molecules' intermolecular hydrogen bonds and packing. In this way, several functionalities of these new resveratrol hybrids were examined as a necessary approach to finding more effective drugs for complicated neurodegenerative diseases.

Keywords: cholinesterase inhibitory activity; molecular docking; pyran-4-ones; thienostilbenes.

MeSH terms

  • Alzheimer Disease* / metabolism
  • Antioxidants / chemistry
  • Antioxidants / pharmacology
  • Chelating Agents / chemistry
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacology
  • Cholinesterases / metabolism
  • Galantamine
  • Humans
  • Ligands
  • Molecular Docking Simulation
  • Pyrones
  • Resveratrol
  • Structure-Activity Relationship
  • Thiophenes
  • Trace Elements*

Substances

  • Antioxidants
  • Chelating Agents
  • Cholinesterase Inhibitors
  • Ligands
  • Pyrones
  • Thiophenes
  • Trace Elements
  • Galantamine
  • maltol
  • Cholinesterases
  • Resveratrol

Grants and funding

This work was supported by grants from the University of Zagreb for short-term scientific support for 2021 under the title Synthesis and photochemistry of various new heterostilbene derivatives. We also acknowledge the NMR Centre at RBI for recording all the NMR spectra. We thank the University of Zagreb Computing Centre (SRCE) for granting computational time on the ISABELLA cluster. This work has been implemented by the TKP2021-NKTA-21 project with the support provided by the Ministry of Culture and Innovation of Hungary from the National Research, Development and Innovation Fund, financed under the 2021 Thematic Excellence Programme funding scheme.