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dc.creatorBautista-Aguilera, Oscar M.
dc.creatorEsteban, Gerard
dc.creatorChioua, Mourad
dc.creatorNikolić, Katarina
dc.creatorAgbaba, Danica
dc.creatorMoraleda, Ignacio
dc.creatorIriepa, Isabel
dc.creatorSoriano, Elena
dc.creatorSamadi, Abdelouahid
dc.creatorUnzeta, Mercedes
dc.creatorMarco-Contelles, Jose
dc.date.accessioned2019-09-02T11:38:38Z
dc.date.available2019-09-02T11:38:38Z
dc.date.issued2014
dc.identifier.issn1177-8881
dc.identifier.urihttp://farfar.pharmacy.bg.ac.rs/handle/123456789/2083
dc.description.abstractThe 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.en
dc.publisherDove Medical Press Ltd, Albany
dc.relationEU COST Action CM 1103
dc.rightsopenAccess
dc.sourceDrug Design Development and Therapy
dc.subjectdonepezil-pyridyl hybridsen
dc.subjectChEen
dc.subjectMAOen
dc.subject3D-QSARen
dc.subjectmolecular modelingen
dc.subjectADMETen
dc.titleMultipotent 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 hybridsen
dc.typearticle
dc.rights.licenseBY-NC
dcterms.abstractНиколић, Катарина; Унзета, Мерцедес; Aгбаба, Даница; Мораледа, Игнацио; Ириепа, Исабел; Баутиста-Aгуилера, Осцар М.; Естебан, Герард; Цхиоуа, Моурад; Марцо-Цонтеллес, Јосе; Самади, Aбделоуахид; Сориано, Елена;
dc.citation.volume8
dc.citation.spage1893
dc.citation.epage1910
dc.citation.other8: 1893-1910
dc.citation.rankM21
dc.identifier.wos000343104500001
dc.identifier.doi10.2147/DDDT.S69258
dc.identifier.pmid25378907
dc.identifier.scopus2-s2.0-84908079484
dc.identifier.fulltexthttp://farfar.pharmacy.bg.ac.rs//bitstream/id/824/2081.pdf
dc.identifier.rcubconv_3177
dc.type.versionpublishedVersion


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