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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.
J Med Chem. 2011 Dec 22; 54(24):8251-70.JM

Abstract

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.

Authors+Show Affiliations

Departament de Bioquı́mica i Biologı́a Molecular, Facultat de Medicina, Institut de Neurociències, Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22023459

Citation

Bolea, Irene, et al. "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." Journal of Medicinal Chemistry, vol. 54, no. 24, 2011, pp. 8251-70.
Bolea I, Juárez-Jiménez J, de Los Ríos C, et al. 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. J Med Chem. 2011;54(24):8251-70.
Bolea, I., Juárez-Jiménez, J., de Los Ríos, C., Chioua, M., Pouplana, R., Luque, F. J., Unzeta, M., Marco-Contelles, J., & Samadi, A. (2011). 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. Journal of Medicinal Chemistry, 54(24), 8251-70. https://doi.org/10.1021/jm200853t
Bolea I, et al. 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. J Med Chem. 2011 Dec 22;54(24):8251-70. PubMed PMID: 22023459.
* Article titles in AMA citation format should be in sentence-case
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, Y1 - 2011/11/15/ PY - 2011/10/26/entrez PY - 2011/10/26/pubmed PY - 2012/3/9/medline SP - 8251 EP - 70 JF - Journal of medicinal chemistry JO - J Med Chem VL - 54 IS - 24 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 (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. SN - 1520-4804 UR - https://www.unboundmedicine.com/medline/citation/22023459/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_ L2 - https://doi.org/10.1021/jm200853t DB - PRIME DP - Unbound Medicine ER -