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
Samo za registrovane korisnike
2014
Autori
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
Članak u časopisu (Objavljena verzija)
Metapodaci
Prikaz svih podataka o dokumentuApstrakt
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.
Ključne reči:
Donepezil / Donepezil-indolyl hybrids / EeAChE / eqBuChE / hMAO A / hMAO B / Inhibitors / 3D-QSAR / Molecular modeling / ADMETIzvor:
European Journal of Medicinal Chemistry, 2014, 75, 82-95Izdavač:
- Elsevier France-Editions Scientifiques Medicales Elsevier, Issy-Les-Moulineaux
Finansiranje / projekti:
- 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
Institucija/grupa
PharmacyTY - 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 . .