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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
dc.creator | Bautista-Aguilera, Oscar M. | |
dc.creator | Esteban, Gerard | |
dc.creator | Chioua, Mourad | |
dc.creator | Nikolić, Katarina | |
dc.creator | Agbaba, Danica | |
dc.creator | Moraleda, Ignacio | |
dc.creator | Iriepa, Isabel | |
dc.creator | Soriano, Elena | |
dc.creator | Samadi, Abdelouahid | |
dc.creator | Unzeta, Mercedes | |
dc.creator | Marco-Contelles, Jose | |
dc.date.accessioned | 2019-09-02T11:38:38Z | |
dc.date.available | 2019-09-02T11:38:38Z | |
dc.date.issued | 2014 | |
dc.identifier.issn | 1177-8881 | |
dc.identifier.uri | https://farfar.pharmacy.bg.ac.rs/handle/123456789/2083 | |
dc.description.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. | en |
dc.publisher | Dove Medical Press Ltd, Albany | |
dc.relation | EU COST Action CM 1103 | |
dc.rights | openAccess | |
dc.rights.uri | https://creativecommons.org/licenses/by-nc/4.0/ | |
dc.source | Drug Design Development and Therapy | |
dc.subject | donepezil-pyridyl hybrids | en |
dc.subject | ChE | en |
dc.subject | MAO | en |
dc.subject | 3D-QSAR | en |
dc.subject | molecular modeling | en |
dc.subject | ADMET | en |
dc.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 | en |
dc.type | article | |
dc.rights.license | BY-NC | |
dcterms.abstract | Николић, 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.volume | 8 | |
dc.citation.spage | 1893 | |
dc.citation.epage | 1910 | |
dc.citation.other | 8: 1893-1910 | |
dc.citation.rank | M21 | |
dc.identifier.wos | 000343104500001 | |
dc.identifier.doi | 10.2147/DDDT.S69258 | |
dc.identifier.pmid | 25378907 | |
dc.identifier.scopus | 2-s2.0-84908079484 | |
dc.identifier.fulltext | https://farfar.pharmacy.bg.ac.rs//bitstream/id/824/2081.pdf | |
dc.type.version | publishedVersion |