Synthesis, biological evaluation, and molecular modeling of donepezil and N-[(5-(benzyloxy)-1-methyl-1H-indol-2-yl)methyl]-N-methylprop-2-yn-1-amine hybrids as new multipotent cholinesterase/monoamine oxidase inhibitors for the treatment of Alzheimer's disease.
A new family of multitarget molecules able to interact with acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), as well as with monoamino oxidase (MAO) A and B, has been synthesized. Novel compounds (3-9) have been designed using a conjunctive approach that combines the benzylpiperidine moiety of the AChE inhibitor donepezil (1) and the indolyl propargylamino moiety of the MAO inhibitor N-[(5-benzyloxy-1-methyl-1H-indol-2-yl)methyl]-N-methylprop-2-yn-1-amine (2), connected through an oligomethylene linker. The most promising hybrid (5) is a potent inhibitor of both MAO-A (IC50=5.2±1.1 nM) and MAO-B (IC50=43±8.0 nM) and is a moderately potent inhibitor of AChE (IC50=0.35±0.01 μM) and BuChE (IC50=0.46±0.06 μM). Moreover, molecular modeling and kinetic studies support the dual binding site to AChE, which explains the inhibitory effect exerted on Aβ aggregation. Overall, the results suggest that the new compounds are promising multitarget drug candidates with potential impact for Alzheimer's disease therapy.
Departament de Bioquı́mica i Biologı́a Molecular, Facultat de Medicina, Institut de Neurociències, Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain.
Irene
I
Bolea
Jordi
J
Juárez-Jiménez
Cristóbal
C
de Los Ríos
Mourad
M
Chioua
Ramón
R
Pouplana
F Javier
FJ
Luque
Mercedes
M
Unzeta
José
J
Marco-Contelles
Abdelouahid
A
Samadi
D000110:Acetylcholinesterase / Q000737:chemistry / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy*; D016229:Amyloid beta-Peptides / Q000737:chemistry; D000818:Animals; D001665:Binding Sites; D002091:Butyrylcholinesterase / Q000737:chemistry / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000077265:Donepezil; D004593:Electrophorus; D006736:Horses; D006801:Humans; D007189:Indans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007527:Isoenzymes / Q000737:chemistry; D007700:Kinetics; D008958:Models, Molecular; D008995:Monoamine Oxidase / Q000737:chemistry; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010446:Peptide Fragments / Q000737:chemistry; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
D016229:Amyloid beta-Peptides; D002800:Cholinesterase Inhibitors; D007189:Indans; D007211:Indoles; D007527:Isoenzymes; D008996:Monoamine Oxidase Inhibitors; C570530:N-((5-(3-(1-benzylpiperidin-4-yl)propoxy)-1-methyl-1H-indol-2-yl)methyl)-N-methylprop-2-yn-1-amine; D010446:Peptide Fragments; D010880:Piperidines; C075222:amyloid beta-protein (1-42); D000077265:Donepezil; D008995:Monoamine Oxidase; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase