Bifunctional phenolic-choline conjugates as anti-oxidants and acetylcholinesterase inhibitors

Abstract

Because of the complex cascade of molecular events that can occur in the brain of an Alzheimer’s disease (AD) patient, the therapy of this neurodegenerative disease seems more likely to be achieved by multifunctional drugs. Herein, a new series of dual-targeting ligands have been developed and in vitro bioevaluated. Their architecture is based on conjugating the acetylcholinesterase inhibition and anti-oxidant properties in one molecular entity. Specifically, a series of naturally occurring phenolic acids with recognized anti-oxidant properties (derivatives of caffeic acid, rosmarinic acid, and trolox) have been conjugated with choline to account for the recognition by acetylcholinesterase (AChE). The synthesized hybrid compounds evidenced AChE inhibitory capacity of micromolar range (rationalized by molecular modeling studies) and good antioxidant properties. Their effects on human neuroblastoma cells, previously treated with beta-amyloid peptides and 1-methyl-4-phenylpyridinium ion neurotoxins (to simulate AD and Parkinson’s disease, respectively), also demonstrated a considerable capacity for protection against the cytotoxicity of these stressors.

Keywords::

• Acetylcholinesterase inhibitors
• antioxidants
• hybrid ligands
• anti-neurodegeneratives
• Alzheimer’s disease

Acknowledgements

The authors thank Portuguese NMR Network (IST-UTL Center) for providing access to the NMR facility. The mass spectra were obtained at the IST Node, which is part of the National Mass Spectrometry Network (RNEM) created by the Portuguese Foundation for Science and Technology (FCT). The authors thank Leonel Gil Nogueira for helping with Ionex HPLC.

Declaration of interest

The authors are grateful to the Portuguese Foundation for Science and Technology (FCT) (Postdoc grant SFRH/BPD/42511/2007, PhD grant SFRH/BD/37547/2007, PhD grant SFRH/BD/32470/2006, and PhD grant SFRH/BD/38743/2007) for financial support. The authors are also thankful to Centro de Neurociências e Biologia Celular da Universidade de Coimbra (Portugal) for financial support. All molecular modeling figures were produced using the UCSF Chimera package from the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco (supported by NIH Grant P41 RR-01081).