Bifunctional phenolic-choline conjugates as anti-oxidants and acetylcholinesterase inhibitors.
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.
Centro de Química Estrutural, Instituto Superior Técnico, Av. Rovisco Pais 1, 1049-001 Lisboa, Portugal.
Jaroslav
J
Sebestík
Sérgio M
SM
Marques
Pedro L
PL
Falé
Susana
S
Santos
Daniela M
DM
Arduíno
Sandra M
SM
Cardoso
Catarina R
CR
Oliveira
M Luísa M
ML
Serralheiro
M Amélia
MA
Santos
D000110:Acetylcholinesterase / Q000378:metabolism*; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002794:Choline / Q000737:chemistry / Q000494:pharmacology*; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D010636:Phenols / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000975:Antioxidants; D002800:Cholinesterase Inhibitors; D010636:Phenols; D000110:Acetylcholinesterase; D002794:Choline