Multi-target-directed drug design strategy: from a dual binding site acetylcholinesterase inhibitor to a trifunctional compound against Alzheimer's disease.
A design strategy to convert a dual-binding site AChE inhibitor into triple functional compounds with promising in vitro profile against multifactorial syndromes, such as Alzheimer's disease, is proposed. The lead compound bis(7)-tacrine (2) was properly modified to confer to the new molecules the ability of chelating metals, involved in the neurodegenerative process. The multifunctional compounds show activity against human AChE, are able to inhibit the AChE-induced amyloid-beta aggregation, and chelate metals, such as iron and copper.
Department of Pharmaceutical Sciences, A. Mangini, Alma Mater Studiorum, Bologna University, Italy. marialaura.bolognesi@unibo.it
Maria Laura
ML
Bolognesi
Andrea
A
Cavalli
Luca
L
Valgimigli
Manuela
M
Bartolini
Michela
M
Rosini
Vincenza
V
Andrisano
Maurizio
M
Recanatini
Carlo
C
Melchiorre
D000110:Acetylcholinesterase / Q000737:chemistry*; D000544:Alzheimer Disease / Q000188:drug therapy*; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D001665:Binding Sites; D002091:Butyrylcholinesterase / Q000737:chemistry; D002614:Chelating Agents / Q000138:chemical synthesis / Q000737:chemistry; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D003300:Copper / Q000737:chemistry; D015195:Drug Design; D005290:Ferric Compounds / Q000737:chemistry; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D010446:Peptide Fragments / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013619:Tacrine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry; D013816:Thermodynamics
D016229:Amyloid beta-Peptides; D002614:Chelating Agents; D002800:Cholinesterase Inhibitors; D005290:Ferric Compounds; D008024:Ligands; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); D013619:Tacrine; D003300:Copper; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; C029892:cupric chloride