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Design, synthesis, pharmacological evaluation, QSAR analysis, molecular modeling and ADMET of novel donepezil-indolyl hybrids as multipotent cholinesterase/monoamine oxidase inhibitors for the potential treatment of Alzheimer's disease

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2014
Authors
Bautista-Aguilera, Oscar M.
Esteban, Gerard
Bolea, Irene
Nikolić, Katarina
Agbaba, Danica
Moraleda, Ignacio
Iriepa, Isabel
Samadi, Abdelouahid
Soriano, Elena
Unzeta, Mercedes
Marco-Contelles, Jose
Article (Published version)
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Abstract
The design, synthesis, and pharmacological evaluation of donepezil indolyl based amines 7-10, amides 12-16, and carboxylic acid derivatives 5 and 11, as multipotent ASS234 analogs, able to inhibit simultaneously cholinesterase (ChE) and monoamine oxidase (MAO) enzymes for the potential treatment of Alzheimer's disease (AD), is reported. Theoretical studies using 3D-Quantitative Structure Activity Relationship (3D-QSAR) was used to define 3D-pharmacophores for inhibition of MAO A/B, AChE, and BuChE enzymes. We found that, in general, and for the same substituent, amines are more potent ChE inhibitors (see compounds 12, 13 versus 7 and 8) or equipotent (see compounds 14, 15 versus 9 and 10) than the corresponding amides, showing a clear EeAChE inhibition selectivity. For the MAO inhibition, amides were not active, and among the amines, compound 14 was totally MAO A selective, while amines 15 and 16 were quite MAO A selective. Carboxylic acid derivatives 5 and 11 showed a multipotent mode...rate selective profile as EeACE and MAO A inhibitors. Propargylamine 15 [N-((5-(3-(1-benzylpiperidin-4-yl)propoxy)-1-methyl-1H-indol-2-yl)methyl)prop-2-yn-1-amine] resulted in the most potent hMAO A (IC50 = 5.5 +/- 1.4 nM) and moderately potent hMAO B (IC50 = 150 +/- 31 nM), EeAChE (IC50 = 190 +/- 10 nM), and eqBuChE (IC50 = 830 +/- 160 nM) inhibitor. However, the analogous N-allyl and the N-morpholine derivatives 16 and 14 deserve also attention as they show an attractive multipotent profile. To sum up, donepezil indolyl hybrid 15 is a promising drug for further development for the potential prevention and treatment of AD.

Keywords:
Donepezil / Donepezil-indolyl hybrids / EeAChE / eqBuChE / hMAO A / hMAO B / Inhibitors / 3D-QSAR / Molecular modeling / ADMET
Source:
European Journal of Medicinal Chemistry, 2014, 75, 82-95
Publisher:
  • Elsevier France-Editions Scientifiques Medicales Elsevier, Issy-Les-Moulineaux
Funding / projects:
  • EU COST Action CM 1103

DOI: 10.1016/j.ejmech.2013.12.028

ISSN: 0223-5234

PubMed: 24530494

WoS: 000333775600009

Scopus: 2-s2.0-84893943097
[ Google Scholar ]
113
100
URI
https://farfar.pharmacy.bg.ac.rs/handle/123456789/2158
Collections
  • Radovi istraživača / Researchers’ publications
Institution/Community
Pharmacy
TY  - JOUR
AU  - Bautista-Aguilera, Oscar M.
AU  - Esteban, Gerard
AU  - Bolea, Irene
AU  - Nikolić, Katarina
AU  - Agbaba, Danica
AU  - Moraleda, Ignacio
AU  - Iriepa, Isabel
AU  - Samadi, Abdelouahid
AU  - Soriano, Elena
AU  - Unzeta, Mercedes
AU  - Marco-Contelles, Jose
PY  - 2014
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2158
AB  - The design, synthesis, and pharmacological evaluation of donepezil indolyl based amines 7-10, amides 12-16, and carboxylic acid derivatives 5 and 11, as multipotent ASS234 analogs, able to inhibit simultaneously cholinesterase (ChE) and monoamine oxidase (MAO) enzymes for the potential treatment of Alzheimer's disease (AD), is reported. Theoretical studies using 3D-Quantitative Structure Activity Relationship (3D-QSAR) was used to define 3D-pharmacophores for inhibition of MAO A/B, AChE, and BuChE enzymes. We found that, in general, and for the same substituent, amines are more potent ChE inhibitors (see compounds 12, 13 versus 7 and 8) or equipotent (see compounds 14, 15 versus 9 and 10) than the corresponding amides, showing a clear EeAChE inhibition selectivity. For the MAO inhibition, amides were not active, and among the amines, compound 14 was totally MAO A selective, while amines 15 and 16 were quite MAO A selective. Carboxylic acid derivatives 5 and 11 showed a multipotent moderate selective profile as EeACE and MAO A inhibitors. Propargylamine 15 [N-((5-(3-(1-benzylpiperidin-4-yl)propoxy)-1-methyl-1H-indol-2-yl)methyl)prop-2-yn-1-amine] resulted in the most potent hMAO A (IC50 = 5.5 +/- 1.4 nM) and moderately potent hMAO B (IC50 = 150 +/- 31 nM), EeAChE (IC50 = 190 +/- 10 nM), and eqBuChE (IC50 = 830 +/- 160 nM) inhibitor. However, the analogous N-allyl and the N-morpholine derivatives 16 and 14 deserve also attention as they show an attractive multipotent profile. To sum up, donepezil indolyl hybrid 15 is a promising drug for further development for the potential prevention and treatment of AD.
PB  - Elsevier France-Editions Scientifiques Medicales Elsevier, Issy-Les-Moulineaux
T2  - European Journal of Medicinal Chemistry
T1  - Design, synthesis, pharmacological evaluation, QSAR analysis, molecular modeling and ADMET of novel donepezil-indolyl hybrids as multipotent cholinesterase/monoamine oxidase inhibitors for the potential treatment of Alzheimer's disease
VL  - 75
SP  - 82
EP  - 95
DO  - 10.1016/j.ejmech.2013.12.028
ER  - 
@article{
author = "Bautista-Aguilera, Oscar M. and Esteban, Gerard and Bolea, Irene and Nikolić, Katarina and Agbaba, Danica and Moraleda, Ignacio and Iriepa, Isabel and Samadi, Abdelouahid and Soriano, Elena and Unzeta, Mercedes and Marco-Contelles, Jose",
year = "2014",
abstract = "The design, synthesis, and pharmacological evaluation of donepezil indolyl based amines 7-10, amides 12-16, and carboxylic acid derivatives 5 and 11, as multipotent ASS234 analogs, able to inhibit simultaneously cholinesterase (ChE) and monoamine oxidase (MAO) enzymes for the potential treatment of Alzheimer's disease (AD), is reported. Theoretical studies using 3D-Quantitative Structure Activity Relationship (3D-QSAR) was used to define 3D-pharmacophores for inhibition of MAO A/B, AChE, and BuChE enzymes. We found that, in general, and for the same substituent, amines are more potent ChE inhibitors (see compounds 12, 13 versus 7 and 8) or equipotent (see compounds 14, 15 versus 9 and 10) than the corresponding amides, showing a clear EeAChE inhibition selectivity. For the MAO inhibition, amides were not active, and among the amines, compound 14 was totally MAO A selective, while amines 15 and 16 were quite MAO A selective. Carboxylic acid derivatives 5 and 11 showed a multipotent moderate selective profile as EeACE and MAO A inhibitors. Propargylamine 15 [N-((5-(3-(1-benzylpiperidin-4-yl)propoxy)-1-methyl-1H-indol-2-yl)methyl)prop-2-yn-1-amine] resulted in the most potent hMAO A (IC50 = 5.5 +/- 1.4 nM) and moderately potent hMAO B (IC50 = 150 +/- 31 nM), EeAChE (IC50 = 190 +/- 10 nM), and eqBuChE (IC50 = 830 +/- 160 nM) inhibitor. However, the analogous N-allyl and the N-morpholine derivatives 16 and 14 deserve also attention as they show an attractive multipotent profile. To sum up, donepezil indolyl hybrid 15 is a promising drug for further development for the potential prevention and treatment of AD.",
publisher = "Elsevier France-Editions Scientifiques Medicales Elsevier, Issy-Les-Moulineaux",
journal = "European Journal of Medicinal Chemistry",
title = "Design, synthesis, pharmacological evaluation, QSAR analysis, molecular modeling and ADMET of novel donepezil-indolyl hybrids as multipotent cholinesterase/monoamine oxidase inhibitors for the potential treatment of Alzheimer's disease",
volume = "75",
pages = "82-95",
doi = "10.1016/j.ejmech.2013.12.028"
}
Bautista-Aguilera, O. M., Esteban, G., Bolea, I., Nikolić, K., Agbaba, D., Moraleda, I., Iriepa, I., Samadi, A., Soriano, E., Unzeta, M.,& Marco-Contelles, J.. (2014). Design, synthesis, pharmacological evaluation, QSAR analysis, molecular modeling and ADMET of novel donepezil-indolyl hybrids as multipotent cholinesterase/monoamine oxidase inhibitors for the potential treatment of Alzheimer's disease. in European Journal of Medicinal Chemistry
Elsevier France-Editions Scientifiques Medicales Elsevier, Issy-Les-Moulineaux., 75, 82-95.
https://doi.org/10.1016/j.ejmech.2013.12.028
Bautista-Aguilera OM, Esteban G, Bolea I, Nikolić K, Agbaba D, Moraleda I, Iriepa I, Samadi A, Soriano E, Unzeta M, Marco-Contelles J. Design, synthesis, pharmacological evaluation, QSAR analysis, molecular modeling and ADMET of novel donepezil-indolyl hybrids as multipotent cholinesterase/monoamine oxidase inhibitors for the potential treatment of Alzheimer's disease. in European Journal of Medicinal Chemistry. 2014;75:82-95.
doi:10.1016/j.ejmech.2013.12.028 .
Bautista-Aguilera, Oscar M., Esteban, Gerard, Bolea, Irene, Nikolić, Katarina, Agbaba, Danica, Moraleda, Ignacio, Iriepa, Isabel, Samadi, Abdelouahid, Soriano, Elena, Unzeta, Mercedes, Marco-Contelles, Jose, "Design, synthesis, pharmacological evaluation, QSAR analysis, molecular modeling and ADMET of novel donepezil-indolyl hybrids as multipotent cholinesterase/monoamine oxidase inhibitors for the potential treatment of Alzheimer's disease" in European Journal of Medicinal Chemistry, 75 (2014):82-95,
https://doi.org/10.1016/j.ejmech.2013.12.028 . .

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