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dc.creatorBautista-Aguilera, Oscar M.
dc.creatorEsteban, Gerard
dc.creatorBolea, Irene
dc.creatorNikolić, Katarina
dc.creatorAgbaba, Danica
dc.creatorMoraleda, Ignacio
dc.creatorIriepa, Isabel
dc.creatorSamadi, Abdelouahid
dc.creatorSoriano, Elena
dc.creatorUnzeta, Mercedes
dc.creatorMarco-Contelles, Jose
dc.date.accessioned2019-09-02T11:40:31Z
dc.date.available2019-09-02T11:40:31Z
dc.date.issued2014
dc.identifier.issn0223-5234
dc.identifier.urihttp://farfar.pharmacy.bg.ac.rs/handle/123456789/2158
dc.description.abstractThe 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.en
dc.publisherElsevier France-Editions Scientifiques Medicales Elsevier, Issy-Les-Moulineaux
dc.relationEU COST Action CM 1103
dc.rightsrestrictedAccess
dc.sourceEuropean Journal of Medicinal Chemistry
dc.subjectDonepezilen
dc.subjectDonepezil-indolyl hybridsen
dc.subjectEeAChEen
dc.subjecteqBuChEen
dc.subjecthMAO Aen
dc.subjecthMAO Ben
dc.subjectInhibitorsen
dc.subject3D-QSARen
dc.subjectMolecular modelingen
dc.subjectADMETen
dc.titleDesign, 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 diseaseen
dc.typearticle
dc.rights.licenseARR
dcterms.abstractСамади, Aбделоуахид; Марцо-Цонтеллес, Јосе; Естебан, Герард; Aгбаба, Даница; Николић, Катарина; Болеа, Ирене; Унзета, Мерцедес; Баутиста-Aгуилера, Осцар М.; Сориано, Елена; Мораледа, Игнацио; Ириепа, Исабел;
dc.citation.volume75
dc.citation.spage82
dc.citation.epage95
dc.citation.other75: 82-95
dc.citation.rankM21
dc.identifier.wos000333775600009
dc.identifier.doi10.1016/j.ejmech.2013.12.028
dc.identifier.pmid24530494
dc.identifier.scopus2-s2.0-84893943097
dc.identifier.rcubconv_3047
dc.type.versionpublishedVersion


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