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.
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.
authors: Laboratorio de Química Médica (IQOG, CSIC), C/Juan de la Cierva 3, 28006 Madrid, Spain.
authors: Oscar M
authors: OM
authors: Bautista-Aguilera
authors: Departament de Bioquímica i Biología Molecular, Facultat de Medicina, Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain.
authors: Gerard
authors: G
authors: Esteban
authors: Departament de Bioquímica i Biología Molecular, Facultat de Medicina, Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain.
authors: Irene
authors: I
authors: Bolea
authors: Institute of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11000 Belgrade, Serbia.
authors: Katarina
authors: K
authors: Nikolic
authors: Institute of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11000 Belgrade, Serbia.
authors: Danica
authors: D
authors: Agbaba
authors: Departamento de Química Orgánica, Facultad de Farmacia, Universidad de Alcalá, Ctra. Barcelona, Km. 33.5, 28817 Alcalá de Henares, Spain.
authors: Ignacio
authors: I
authors: Moraleda
authors: Departamento de Química Orgánica, Facultad de Farmacia, Universidad de Alcalá, Ctra. Barcelona, Km. 33.5, 28817 Alcalá de Henares, Spain.
authors: Isabel
authors: I
authors: Iriepa
authors: Laboratorio de Química Médica (IQOG, CSIC), C/Juan de la Cierva 3, 28006 Madrid, Spain.
authors: Abdelouahid
authors: A
authors: Samadi
authors: SEPCO, (IQOG, CSIC), C/Juan de la Cierva 3, 28006 Madrid, Spain.
authors: Elena
authors: E
authors: Soriano
authors: Departament de Bioquímica i Biología Molecular, Facultat de Medicina, Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain.
authors: Mercedes
authors: M
authors: Unzeta
authors: Laboratorio de Química Médica (IQOG, CSIC), C/Juan de la Cierva 3, 28006 Madrid, Spain. Electronic address: iqoc21@iqog.csic.es.
authors: José
authors: J
authors: Marco-Contelles
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology*; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D002802:Cholinesterases / Q000737:chemistry / Q000378:metabolism; D000077265:Donepezil; D015195:Drug Design; D004593:Electrophorus; D006736:Horses; D006801:Humans; D007189:Indans / Q000737:chemistry* / Q000494:pharmacology; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology; D008958:Models, Molecular; D008995:Monoamine Oxidase / Q000737:chemistry / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D010880:Piperidines / Q000737:chemistry* / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship
chemical_list: D002800:Cholinesterase Inhibitors; D007189:Indans; D007211:Indoles; D008996:Monoamine Oxidase Inhibitors; D010880:Piperidines; D000077265:Donepezil; D008995:Monoamine Oxidase; D002802:Cholinesterases
keywords: 3D-QSAR; ADMET; Donepezil; Donepezil–indolyl hybrids; EeAChE; Inhibitors; Molecular modeling; eqBuChE; hMAO A; hMAO B