TY - JOUR
T1 - 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
AU - Bolea, Irene
AU - Juárez-Jiménez, Jordi
AU - De Los Ríos, Cristóbal
AU - Chioua, Mourad
AU - Pouplana, Ramón
AU - Luque, F. Javier
AU - Unzeta, Mercedes
AU - Marco-Contelles, José
AU - Samadi, Abdelouahid
PY - 2011/12/22
Y1 - 2011/12/22
N2 - 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 (IC 50 = 5.2 ± 1.1 nM) and MAO-B (IC 50 = 43 ± 8.0 nM) and is a moderately potent inhibitor of AChE (IC 50 = 0.35 ± 0.01 μM) and BuChE (IC 50 = 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. (Figure presented)
AB - 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 (IC 50 = 5.2 ± 1.1 nM) and MAO-B (IC 50 = 43 ± 8.0 nM) and is a moderately potent inhibitor of AChE (IC 50 = 0.35 ± 0.01 μM) and BuChE (IC 50 = 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. (Figure presented)
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U2 - 10.1021/jm200853t
DO - 10.1021/jm200853t
M3 - Article
C2 - 22023459
AN - SCOPUS:84055217642
SN - 0022-2623
VL - 54
SP - 8251
EP - 8270
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 24
ER -