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Multipotent cholinesterase/monoamine oxidase inhibitors for the treatment of Alzheimer's disease: design, synthesis, biochemical evaluation, ADMET, molecular modeling, and QSAR analysis of novel donepezil-pyridyl hybrids

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2014
2081.pdf (3.136Mb)
Authors
Bautista-Aguilera, Oscar M.
Esteban, Gerard
Chioua, Mourad
Nikolić, Katarina
Agbaba, Danica
Moraleda, Ignacio
Iriepa, Isabel
Soriano, Elena
Samadi, Abdelouahid
Unzeta, Mercedes
Marco-Contelles, Jose
Article (Published version)
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Abstract
The design, synthesis, and biochemical evaluation of donepezil-pyridyl hybrids (DPHs) as multipotent cholinesterase (ChE) and monoamine oxidase (MAO) inhibitors for the potential treatment of Alzheimer's disease (AD) is reported. The 3D-quantitative structure-activity relationship study was used to define 3D-pharmacophores for inhibition of MAO A/B, acetylcholinesterase (AChE), and butyrylcholinesterase (BuChE) enzymes and to design DPHs as novel multi-target drug candidates with potential impact in the therapy of AD. DPH14 (Electrophorus electricus AChE [EeAChE]: half maximal inhibitory concentration [IC50] = 1.1 +/- 0.3 nM; equine butyrylcholinesterase [eqBuChE]: IC50 = 600 +/- 80 nM) was 318-fold more potent for the inhibition of AChE, and 1.3-fold less potent for the inhibition of BuChE than the reference compound ASS234. DPH14 is a potent human recombinant BuChE (hBuChE) inhibitor, in the same range as DPH12 or DPH16, but 13.1-fold less potent than DPH15 for the inhibition of huma...n recombinant AChE (hAChE). Compared with donepezil, DPH14 is almost equipotent for the inhibition of hAChE, and 8.8-fold more potent for hBuChE. Concerning human monoamine oxidase (hMAO) A inhibition, only DPH9 and 5 proved active, compound DPH9 being the most potent (IC50 [MAO A] = 5,700 +/- 2,100 nM). For hMAO B, only DPHs 13 and 14 were moderate inhibitors, and compound DPH14 was the most potent (IC50 [MAO B] = 3,950 +/- 94 nM). Molecular modeling of inhibitor DPH14 within EeAChE showed a binding mode with an extended conformation, interacting simultaneously with both catalytic and peripheral sites of EeAChE thanks to a linker of appropriate length. Absortion, distribution, metabolism, excretion and toxicity analysis showed that structures lacking phenyl-substituent show better druglikeness profiles; in particular, DPHs13-15 showed the most suitable absortion, distribution, metabolism, excretion and toxicity properties. Novel donepezil-pyridyl hybrid DPH14 is a potent, moderately selective hAChE and selective irreversible hMAO B inhibitor which might be considered as a promising compound for further development for the treatment of AD.

Keywords:
donepezil-pyridyl hybrids / ChE / MAO / 3D-QSAR / molecular modeling / ADMET
Source:
Drug Design Development and Therapy, 2014, 8, 1893-1910
Publisher:
  • Dove Medical Press Ltd, Albany
Funding / projects:
  • EU COST Action CM 1103

DOI: 10.2147/DDDT.S69258

ISSN: 1177-8881

PubMed: 25378907

WoS: 000343104500001

Scopus: 2-s2.0-84908079484
[ Google Scholar ]
60
46
URI
https://farfar.pharmacy.bg.ac.rs/handle/123456789/2083
Collections
  • Radovi istraživača / Researchers’ publications
Institution/Community
Pharmacy
TY  - JOUR
AU  - Bautista-Aguilera, Oscar M.
AU  - Esteban, Gerard
AU  - Chioua, Mourad
AU  - Nikolić, Katarina
AU  - Agbaba, Danica
AU  - Moraleda, Ignacio
AU  - Iriepa, Isabel
AU  - Soriano, Elena
AU  - Samadi, Abdelouahid
AU  - Unzeta, Mercedes
AU  - Marco-Contelles, Jose
PY  - 2014
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2083
AB  - The design, synthesis, and biochemical evaluation of donepezil-pyridyl hybrids (DPHs) as multipotent cholinesterase (ChE) and monoamine oxidase (MAO) inhibitors for the potential treatment of Alzheimer's disease (AD) is reported. The 3D-quantitative structure-activity relationship study was used to define 3D-pharmacophores for inhibition of MAO A/B, acetylcholinesterase (AChE), and butyrylcholinesterase (BuChE) enzymes and to design DPHs as novel multi-target drug candidates with potential impact in the therapy of AD. DPH14 (Electrophorus electricus AChE [EeAChE]: half maximal inhibitory concentration [IC50] = 1.1 +/- 0.3 nM; equine butyrylcholinesterase [eqBuChE]: IC50 = 600 +/- 80 nM) was 318-fold more potent for the inhibition of AChE, and 1.3-fold less potent for the inhibition of BuChE than the reference compound ASS234. DPH14 is a potent human recombinant BuChE (hBuChE) inhibitor, in the same range as DPH12 or DPH16, but 13.1-fold less potent than DPH15 for the inhibition of human recombinant AChE (hAChE). Compared with donepezil, DPH14 is almost equipotent for the inhibition of hAChE, and 8.8-fold more potent for hBuChE. Concerning human monoamine oxidase (hMAO) A inhibition, only DPH9 and 5 proved active, compound DPH9 being the most potent (IC50 [MAO A] = 5,700 +/- 2,100 nM). For hMAO B, only DPHs 13 and 14 were moderate inhibitors, and compound DPH14 was the most potent (IC50 [MAO B] = 3,950 +/- 94 nM). Molecular modeling of inhibitor DPH14 within EeAChE showed a binding mode with an extended conformation, interacting simultaneously with both catalytic and peripheral sites of EeAChE thanks to a linker of appropriate length. Absortion, distribution, metabolism, excretion and toxicity analysis showed that structures lacking phenyl-substituent show better druglikeness profiles; in particular, DPHs13-15 showed the most suitable absortion, distribution, metabolism, excretion and toxicity properties. Novel donepezil-pyridyl hybrid DPH14 is a potent, moderately selective hAChE and selective irreversible hMAO B inhibitor which might be considered as a promising compound for further development for the treatment of AD.
PB  - Dove Medical Press Ltd, Albany
T2  - Drug Design Development and Therapy
T1  - Multipotent cholinesterase/monoamine oxidase inhibitors for the treatment of Alzheimer's disease: design, synthesis, biochemical evaluation, ADMET, molecular modeling, and QSAR analysis of novel donepezil-pyridyl hybrids
VL  - 8
SP  - 1893
EP  - 1910
DO  - 10.2147/DDDT.S69258
ER  - 
@article{
author = "Bautista-Aguilera, Oscar M. and Esteban, Gerard and Chioua, Mourad and Nikolić, Katarina and Agbaba, Danica and Moraleda, Ignacio and Iriepa, Isabel and Soriano, Elena and Samadi, Abdelouahid and Unzeta, Mercedes and Marco-Contelles, Jose",
year = "2014",
abstract = "The design, synthesis, and biochemical evaluation of donepezil-pyridyl hybrids (DPHs) as multipotent cholinesterase (ChE) and monoamine oxidase (MAO) inhibitors for the potential treatment of Alzheimer's disease (AD) is reported. The 3D-quantitative structure-activity relationship study was used to define 3D-pharmacophores for inhibition of MAO A/B, acetylcholinesterase (AChE), and butyrylcholinesterase (BuChE) enzymes and to design DPHs as novel multi-target drug candidates with potential impact in the therapy of AD. DPH14 (Electrophorus electricus AChE [EeAChE]: half maximal inhibitory concentration [IC50] = 1.1 +/- 0.3 nM; equine butyrylcholinesterase [eqBuChE]: IC50 = 600 +/- 80 nM) was 318-fold more potent for the inhibition of AChE, and 1.3-fold less potent for the inhibition of BuChE than the reference compound ASS234. DPH14 is a potent human recombinant BuChE (hBuChE) inhibitor, in the same range as DPH12 or DPH16, but 13.1-fold less potent than DPH15 for the inhibition of human recombinant AChE (hAChE). Compared with donepezil, DPH14 is almost equipotent for the inhibition of hAChE, and 8.8-fold more potent for hBuChE. Concerning human monoamine oxidase (hMAO) A inhibition, only DPH9 and 5 proved active, compound DPH9 being the most potent (IC50 [MAO A] = 5,700 +/- 2,100 nM). For hMAO B, only DPHs 13 and 14 were moderate inhibitors, and compound DPH14 was the most potent (IC50 [MAO B] = 3,950 +/- 94 nM). Molecular modeling of inhibitor DPH14 within EeAChE showed a binding mode with an extended conformation, interacting simultaneously with both catalytic and peripheral sites of EeAChE thanks to a linker of appropriate length. Absortion, distribution, metabolism, excretion and toxicity analysis showed that structures lacking phenyl-substituent show better druglikeness profiles; in particular, DPHs13-15 showed the most suitable absortion, distribution, metabolism, excretion and toxicity properties. Novel donepezil-pyridyl hybrid DPH14 is a potent, moderately selective hAChE and selective irreversible hMAO B inhibitor which might be considered as a promising compound for further development for the treatment of AD.",
publisher = "Dove Medical Press Ltd, Albany",
journal = "Drug Design Development and Therapy",
title = "Multipotent cholinesterase/monoamine oxidase inhibitors for the treatment of Alzheimer's disease: design, synthesis, biochemical evaluation, ADMET, molecular modeling, and QSAR analysis of novel donepezil-pyridyl hybrids",
volume = "8",
pages = "1893-1910",
doi = "10.2147/DDDT.S69258"
}
Bautista-Aguilera, O. M., Esteban, G., Chioua, M., Nikolić, K., Agbaba, D., Moraleda, I., Iriepa, I., Soriano, E., Samadi, A., Unzeta, M.,& Marco-Contelles, J.. (2014). Multipotent cholinesterase/monoamine oxidase inhibitors for the treatment of Alzheimer's disease: design, synthesis, biochemical evaluation, ADMET, molecular modeling, and QSAR analysis of novel donepezil-pyridyl hybrids. in Drug Design Development and Therapy
Dove Medical Press Ltd, Albany., 8, 1893-1910.
https://doi.org/10.2147/DDDT.S69258
Bautista-Aguilera OM, Esteban G, Chioua M, Nikolić K, Agbaba D, Moraleda I, Iriepa I, Soriano E, Samadi A, Unzeta M, Marco-Contelles J. Multipotent cholinesterase/monoamine oxidase inhibitors for the treatment of Alzheimer's disease: design, synthesis, biochemical evaluation, ADMET, molecular modeling, and QSAR analysis of novel donepezil-pyridyl hybrids. in Drug Design Development and Therapy. 2014;8:1893-1910.
doi:10.2147/DDDT.S69258 .
Bautista-Aguilera, Oscar M., Esteban, Gerard, Chioua, Mourad, Nikolić, Katarina, Agbaba, Danica, Moraleda, Ignacio, Iriepa, Isabel, Soriano, Elena, Samadi, Abdelouahid, Unzeta, Mercedes, Marco-Contelles, Jose, "Multipotent cholinesterase/monoamine oxidase inhibitors for the treatment of Alzheimer's disease: design, synthesis, biochemical evaluation, ADMET, molecular modeling, and QSAR analysis of novel donepezil-pyridyl hybrids" in Drug Design Development and Therapy, 8 (2014):1893-1910,
https://doi.org/10.2147/DDDT.S69258 . .

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