Interaction of (benzylidene-hydrazono)-1,4-dihydropyridines with beta-amyloid, acetylcholine, and butyrylcholine esterases.
Approved drugs for the treatment of Alzheimer's disease belong to the group of inhibitors of the acetylcholinesterase (AChE) and NMDA receptor inhibitors. However none of the drugs is able to combat or reverse the progression of the disease. Thus, the recently reported promising multitarget-directed molecule approach was applied here. Using the lead compound DUO3, which was found to be a potent inhibitor of the AChE and butyrylcholinesterase (BuChE) as well as an inhibitor of the formation of the amyloid (Abeta) plaque, new non-permanently positively charged derivatives were synthesized and biologically characterized. In contrast to DUO3 the new bisphenyl-substituted pyridinylidene hydrazones 5 are appropriate to cross the blood-brain barrier due to their pK(a) values and lipophilicity, and to inhibit both the AChE and BuChE. More important some of the pyridinylidene hydrazones inhibit the Abeta fibril formation completely and destruct the already formed fibrils significantly.
Faculty of Pharmacy, Ege-University, Bornova-Izmir, Turkey.
Vildan
V
Alptüzün
Michaela
M
Prinz
Verena
V
Hörr
Josef
J
Scheiber
Krzysztof
K
Radacki
Adyary
A
Fallarero
Pia
P
Vuorela
Bernd
B
Engels
Holger
H
Braunschweig
Ercin
E
Erciyas
Ulrike
U
Holzgrabe
D000110:Acetylcholinesterase / Q000737:chemistry* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D001665:Binding Sites; D002091:Butyrylcholinesterase / Q000737:chemistry* / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D003198:Computer Simulation; D004095:Dihydropyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D007700:Kinetics; D008958:Models, Molecular; D013329:Structure-Activity Relationship
D016229:Amyloid beta-Peptides; D002800:Cholinesterase Inhibitors; D004095:Dihydropyridines; C038806:1,4-dihydropyridine; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase