TY  - JOUR
AU  - Ismaili, L
AU  - Refouvelet, B
AU  - Benchekroun, M
AU  - Brogi, S
AU  - Brindisi, M
AU  - Gemma, S
AU  - Campiani, G
AU  - Filipić, Slavica
AU  - Agbaba, Danica
AU  - Esteban, Gerard
AU  - Unzeta, Mercedes
AU  - Nikolić, Katarina
AU  - Butini, Stefania
AU  - Marco-Contelles, Jose
PY  - 2017
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2916
AB  - Alzheimer's disease is a multifactorial and fatal neurodegenerative disorder characterized by decline of cholinergic function, deregulation of other neurotransmitter systems, β-amyloid fibril deposition, and β-amyloid oligomers formation. Based on the involvement of a relevant number of biological systems in Alzheimer's disease progression, multitarget compounds may enable therapeutic efficacy. Accordingly, compounds possessing, besides anticholinergic activity and β-amyloid aggregation inhibition properties, metal chelating and/or nitric oxide releasing properties with additional antioxidant capacity were developed. Other targets relevant to Alzheimer's disease have also been considered in the last years for producing multitarget compounds such as β-secretase, monoamino oxidases, serotonin receptors and sigma 1 receptors. The purpose of this review will be to highlight recent reports on the development of multitarget compounds for Alzheimer's disease published within the last years focusing on multifunctional ligands characterized by tacrine-like and donepezil-like structures.
PB  - Elsevier Ltd
T2  - Progress in Neurobiology
T1  - Multitarget compounds bearing tacrine- and donepezil-like structural and functional motifs for the potential treatment of Alzheimer's disease
VL  - 151
SP  - 4
EP  - 34
DO  - 10.1016/j.pneurobio.2015.12.003
ER  - 

@article{
author = "Ismaili, L and Refouvelet, B and Benchekroun, M and Brogi, S and Brindisi, M and Gemma, S and Campiani, G and Filipić, Slavica and Agbaba, Danica and Esteban, Gerard and Unzeta, Mercedes and Nikolić, Katarina and Butini, Stefania and Marco-Contelles, Jose",
year = "2017",
abstract = "Alzheimer's disease is a multifactorial and fatal neurodegenerative disorder characterized by decline of cholinergic function, deregulation of other neurotransmitter systems, β-amyloid fibril deposition, and β-amyloid oligomers formation. Based on the involvement of a relevant number of biological systems in Alzheimer's disease progression, multitarget compounds may enable therapeutic efficacy. Accordingly, compounds possessing, besides anticholinergic activity and β-amyloid aggregation inhibition properties, metal chelating and/or nitric oxide releasing properties with additional antioxidant capacity were developed. Other targets relevant to Alzheimer's disease have also been considered in the last years for producing multitarget compounds such as β-secretase, monoamino oxidases, serotonin receptors and sigma 1 receptors. The purpose of this review will be to highlight recent reports on the development of multitarget compounds for Alzheimer's disease published within the last years focusing on multifunctional ligands characterized by tacrine-like and donepezil-like structures.",
publisher = "Elsevier Ltd",
journal = "Progress in Neurobiology",
title = "Multitarget compounds bearing tacrine- and donepezil-like structural and functional motifs for the potential treatment of Alzheimer's disease",
volume = "151",
pages = "4-34",
doi = "10.1016/j.pneurobio.2015.12.003"
}

Ismaili, L., Refouvelet, B., Benchekroun, M., Brogi, S., Brindisi, M., Gemma, S., Campiani, G., Filipić, S., Agbaba, D., Esteban, G., Unzeta, M., Nikolić, K., Butini, S.,& Marco-Contelles, J.. (2017). Multitarget compounds bearing tacrine- and donepezil-like structural and functional motifs for the potential treatment of Alzheimer's disease. in Progress in Neurobiology
Elsevier Ltd., 151, 4-34.
https://doi.org/10.1016/j.pneurobio.2015.12.003

Ismaili L, Refouvelet B, Benchekroun M, Brogi S, Brindisi M, Gemma S, Campiani G, Filipić S, Agbaba D, Esteban G, Unzeta M, Nikolić K, Butini S, Marco-Contelles J. Multitarget compounds bearing tacrine- and donepezil-like structural and functional motifs for the potential treatment of Alzheimer's disease. in Progress in Neurobiology. 2017;151:4-34.
doi:10.1016/j.pneurobio.2015.12.003 .

Ismaili, L, Refouvelet, B, Benchekroun, M, Brogi, S, Brindisi, M, Gemma, S, Campiani, G, Filipić, Slavica, Agbaba, Danica, Esteban, Gerard, Unzeta, Mercedes, Nikolić, Katarina, Butini, Stefania, Marco-Contelles, Jose, "Multitarget compounds bearing tacrine- and donepezil-like structural and functional motifs for the potential treatment of Alzheimer's disease" in Progress in Neurobiology, 151 (2017):4-34,
https://doi.org/10.1016/j.pneurobio.2015.12.003 . .

TY  - JOUR
AU  - Nikolić, Katarina
AU  - Mavridis, Lazaros
AU  - Bautista-Aguilera, Oscar M.
AU  - Marco-Contelles, Jose
AU  - Stark, Holger
AU  - Carreiras, Maria do Carmo
AU  - Rossi, Ilaria
AU  - Massarelli, Paola
AU  - Agbaba, Danica
AU  - Ramsay, Rona R.
AU  - Mitchell, John B. O.
PY  - 2015
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2395
AB  - Recently developed multi-targeted ligands are novel drug candidates able to interact with monoamine oxidase A and B; acetylcholinesterase and butyrylcholinesterase; or with histamine N-methyltransferase and histamine H-3-receptor (H3R). These proteins are drug targets in the treatment of depression, Alzheimer's disease, obsessive disorders, and Parkinson's disease. A probabilistic method, the Parzen-Rosenblatt window approach, was used to build a "predictor" model using data collected from the ChEMBL database. The model can be used to predict both the primary pharmaceutical target and off-targets of a compound based on its structure. Molecular structures were represented based on the circular fingerprint methodology. The same approach was used to build a "predictor" model from the DrugBank dataset to determine the main pharmacological groups of the compound. The study of off-target interactions is now recognised as crucial to the understanding of both drug action and toxicology. Primary pharmaceutical targets and off-targets for the novel multi-target ligands were examined by use of the developed cheminformatic method. Several multi-target ligands were selected for further study, as compounds with possible additional beneficial pharmacological activities. The cheminformatic targets identifications were in agreement with four 3D-QSAR (H3R/D1R/D2R/5-HT2aR) models and by in vitro assays for serotonin 5-HT1a and 5-HT2a receptor binding of the most promising ligand (71/MBA-VEG8).
PB  - Springer, Dordrecht
T2  - Journal of Computer-Aided Molecular Design
T1  - Predicting targets of compounds against neurological diseases using cheminformatic methodology
VL  - 29
IS  - 2
SP  - 183
EP  - 198
DO  - 10.1007/s10822-014-9816-1
ER  - 

@article{
author = "Nikolić, Katarina and Mavridis, Lazaros and Bautista-Aguilera, Oscar M. and Marco-Contelles, Jose and Stark, Holger and Carreiras, Maria do Carmo and Rossi, Ilaria and Massarelli, Paola and Agbaba, Danica and Ramsay, Rona R. and Mitchell, John B. O.",
year = "2015",
abstract = "Recently developed multi-targeted ligands are novel drug candidates able to interact with monoamine oxidase A and B; acetylcholinesterase and butyrylcholinesterase; or with histamine N-methyltransferase and histamine H-3-receptor (H3R). These proteins are drug targets in the treatment of depression, Alzheimer's disease, obsessive disorders, and Parkinson's disease. A probabilistic method, the Parzen-Rosenblatt window approach, was used to build a "predictor" model using data collected from the ChEMBL database. The model can be used to predict both the primary pharmaceutical target and off-targets of a compound based on its structure. Molecular structures were represented based on the circular fingerprint methodology. The same approach was used to build a "predictor" model from the DrugBank dataset to determine the main pharmacological groups of the compound. The study of off-target interactions is now recognised as crucial to the understanding of both drug action and toxicology. Primary pharmaceutical targets and off-targets for the novel multi-target ligands were examined by use of the developed cheminformatic method. Several multi-target ligands were selected for further study, as compounds with possible additional beneficial pharmacological activities. The cheminformatic targets identifications were in agreement with four 3D-QSAR (H3R/D1R/D2R/5-HT2aR) models and by in vitro assays for serotonin 5-HT1a and 5-HT2a receptor binding of the most promising ligand (71/MBA-VEG8).",
publisher = "Springer, Dordrecht",
journal = "Journal of Computer-Aided Molecular Design",
title = "Predicting targets of compounds against neurological diseases using cheminformatic methodology",
volume = "29",
number = "2",
pages = "183-198",
doi = "10.1007/s10822-014-9816-1"
}

Nikolić, K., Mavridis, L., Bautista-Aguilera, O. M., Marco-Contelles, J., Stark, H., Carreiras, M. d. C., Rossi, I., Massarelli, P., Agbaba, D., Ramsay, R. R.,& Mitchell, J. B. O.. (2015). Predicting targets of compounds against neurological diseases using cheminformatic methodology. in Journal of Computer-Aided Molecular Design
Springer, Dordrecht., 29(2), 183-198.
https://doi.org/10.1007/s10822-014-9816-1

Nikolić K, Mavridis L, Bautista-Aguilera OM, Marco-Contelles J, Stark H, Carreiras MDC, Rossi I, Massarelli P, Agbaba D, Ramsay RR, Mitchell JBO. Predicting targets of compounds against neurological diseases using cheminformatic methodology. in Journal of Computer-Aided Molecular Design. 2015;29(2):183-198.
doi:10.1007/s10822-014-9816-1 .

Nikolić, Katarina, Mavridis, Lazaros, Bautista-Aguilera, Oscar M., Marco-Contelles, Jose, Stark, Holger, Carreiras, Maria do Carmo, Rossi, Ilaria, Massarelli, Paola, Agbaba, Danica, Ramsay, Rona R., Mitchell, John B. O., "Predicting targets of compounds against neurological diseases using cheminformatic methodology" in Journal of Computer-Aided Molecular Design, 29, no. 2 (2015):183-198,
https://doi.org/10.1007/s10822-014-9816-1 . .

TY  - JOUR
AU  - Bautista-Aguilera, Oscar M.
AU  - Samadi, Abdelouahid
AU  - Chioua, Mourad
AU  - Nikolić, Katarina
AU  - Filipić, Slavica
AU  - Agbaba, Danica
AU  - Soriano, Elena
AU  - de Andres, Lucia
AU  - Isabel Rodriguez-Franco, Maria
AU  - Alcaro, Stefano
AU  - Ramsay, Rona R.
AU  - Ortuso, Francesco
AU  - Yanez, Matilde
AU  - Marco-Contelles, Jose
PY  - 2014
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2113
AB  - On the basis of N-((5-(3-(1-benzylpiperidin-4-yl)propoxy)-1-methyl-1H-indol-2-yl)methyl)-N-methylprop-2-yn-1-amine (II, ASS234) and QSAR predictions, in this work we have designed, synthesized, and evaluated a number of new indole derivatives from which we have identified N-methyl-N-((1-methyl-5-(3-(1-(2-methylbenzyl)piperidin-4-yl)propoxy)-1H-indol-2-yl)methyl)prop-2-yn-1-amine (2, MBA236) as a new cholinesterase and monoamine oxidase dual inhibitor.
PB  - Amer Chemical Soc, Washington
T2  - Journal of Medicinal Chemistry
T1  - N-Methyl-N-((1-methyl-5-(3-(1-(2-methylbenzyl)piperidin-4yl)propoxy)-1H-indol-2-yl)methyl)prop-2-yn-1-amine, a New Cholinesterase and Monoamine Oxidase Dual
VL  - 57
IS  - 24
SP  - 10455
EP  - 10463
DO  - 10.1021/jm501501a
ER  - 

@article{
author = "Bautista-Aguilera, Oscar M. and Samadi, Abdelouahid and Chioua, Mourad and Nikolić, Katarina and Filipić, Slavica and Agbaba, Danica and Soriano, Elena and de Andres, Lucia and Isabel Rodriguez-Franco, Maria and Alcaro, Stefano and Ramsay, Rona R. and Ortuso, Francesco and Yanez, Matilde and Marco-Contelles, Jose",
year = "2014",
abstract = "On the basis of N-((5-(3-(1-benzylpiperidin-4-yl)propoxy)-1-methyl-1H-indol-2-yl)methyl)-N-methylprop-2-yn-1-amine (II, ASS234) and QSAR predictions, in this work we have designed, synthesized, and evaluated a number of new indole derivatives from which we have identified N-methyl-N-((1-methyl-5-(3-(1-(2-methylbenzyl)piperidin-4-yl)propoxy)-1H-indol-2-yl)methyl)prop-2-yn-1-amine (2, MBA236) as a new cholinesterase and monoamine oxidase dual inhibitor.",
publisher = "Amer Chemical Soc, Washington",
journal = "Journal of Medicinal Chemistry",
title = "N-Methyl-N-((1-methyl-5-(3-(1-(2-methylbenzyl)piperidin-4yl)propoxy)-1H-indol-2-yl)methyl)prop-2-yn-1-amine, a New Cholinesterase and Monoamine Oxidase Dual",
volume = "57",
number = "24",
pages = "10455-10463",
doi = "10.1021/jm501501a"
}

Bautista-Aguilera, O. M., Samadi, A., Chioua, M., Nikolić, K., Filipić, S., Agbaba, D., Soriano, E., de Andres, L., Isabel Rodriguez-Franco, M., Alcaro, S., Ramsay, R. R., Ortuso, F., Yanez, M.,& Marco-Contelles, J.. (2014). N-Methyl-N-((1-methyl-5-(3-(1-(2-methylbenzyl)piperidin-4yl)propoxy)-1H-indol-2-yl)methyl)prop-2-yn-1-amine, a New Cholinesterase and Monoamine Oxidase Dual. in Journal of Medicinal Chemistry
Amer Chemical Soc, Washington., 57(24), 10455-10463.
https://doi.org/10.1021/jm501501a

Bautista-Aguilera OM, Samadi A, Chioua M, Nikolić K, Filipić S, Agbaba D, Soriano E, de Andres L, Isabel Rodriguez-Franco M, Alcaro S, Ramsay RR, Ortuso F, Yanez M, Marco-Contelles J. N-Methyl-N-((1-methyl-5-(3-(1-(2-methylbenzyl)piperidin-4yl)propoxy)-1H-indol-2-yl)methyl)prop-2-yn-1-amine, a New Cholinesterase and Monoamine Oxidase Dual. in Journal of Medicinal Chemistry. 2014;57(24):10455-10463.
doi:10.1021/jm501501a .

Bautista-Aguilera, Oscar M., Samadi, Abdelouahid, Chioua, Mourad, Nikolić, Katarina, Filipić, Slavica, Agbaba, Danica, Soriano, Elena, de Andres, Lucia, Isabel Rodriguez-Franco, Maria, Alcaro, Stefano, Ramsay, Rona R., Ortuso, Francesco, Yanez, Matilde, Marco-Contelles, Jose, "N-Methyl-N-((1-methyl-5-(3-(1-(2-methylbenzyl)piperidin-4yl)propoxy)-1H-indol-2-yl)methyl)prop-2-yn-1-amine, a New Cholinesterase and Monoamine Oxidase Dual" in Journal of Medicinal Chemistry, 57, no. 24 (2014):10455-10463,
https://doi.org/10.1021/jm501501a . .

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 . .

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 . .