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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

AuthorsBautista-Aguilera, Óscar M.; Esteban, Gerard; Bolea, Irene; Nikolic, Katarina; Agbaba, Danica; Moraleda, Ignacio; Iriepa, Isabel; Samadi, Abdelouahid ; Soriano, Elena ; Unzeta, Mercedes; Marco-Contelles, José
KeywordsDonepezil
Donepezileindolyl hybrids
EeAChE
eqBuChE
hMAO A
hMAO B
Inhibitors
3D-QSAR
Molecular modeling
ADMET
Issue Date2014
PublisherElsevier
CitationEuropean Journal of Medicinal Chemistry 75: 82- 95 (2014)
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, 13versus7 and 8) or equipotent (see compounds 14, 15versus9 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 (IC 50 = 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. © 2014 Elsevier B.V.
URIhttp://hdl.handle.net/10261/97133
DOI10.1016/j.ejmech.2013.12.028
Identifiersdoi: 10.1016/j.ejmech.2013.12.028
issn: 0223-5234
e-issn: 1768-3254
Appears in Collections:(IQOG) Artículos
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