title: Synthesis, pharmacological assessment, and molecular modeling of acetylcholinesterase/butyrylcholinesterase inhibitors: effect against amyloid-β-induced neurotoxicity.
abstract: The synthesis, molecular modeling, and pharmacological analysis of phenoxyalkylamino-4-phenylnicotinates (2-7), phenoxyalkoxybenzylidenemalononitriles (12, 13), pyridonepezils (14-18), and quinolinodonepezils (19-21) are described. Pyridonepezils 15-18 were found to be selective and moderately potent regarding the inhibition of hAChE, whereas quinolinodonepezils 19-21 were found to be poor inhibitors of hAChE. The most potent and selective hAChE inhibitor was ethyl 6-(4-(1-benzylpiperidin-4-yl)butylamino)-5-cyano-2-methyl-4-phenylnicotinate (18) [IC(50) (hAChE) = 0.25 ± 0.02 μM]. Pyridonepezils 15-18 and quinolinodonepezils 20-21 are more potent selective inhibitors of EeAChE than hAChE. The most potent and selective EeAChE inhibitor was ethyl 6-(2-(1-benzylpiperidin-4-yl)ethylamino)-5-cyano-2-methyl-4-phenylnicotinate (16) [IC(50) (EeAChE) = 0.0167 ± 0.0002 μM], which exhibits the same inhibitory potency as donepezil against hAChE. Compounds 2, 7, 13, 17, 18, 35, and 36 significantly prevented the decrease in cell viability caused by Aβ(1-42). All compounds were effective in preventing the enhancement of AChE activity induced by Aβ(1-42). Compounds 2-7 caused a significant reduction whereas pyridonepezils 17 and 18, and compound 16 also showed some activity. The pyrazolo[3,4-b]quinolines 36 and 38 also prevented the upregulation of AChE induced by Aβ(1-42). Compounds 2, 7, 12, 13, 17, 18, and 36 may act as antagonists of voltage sensitive calcium channels, since they significantly prevented the Ca(2+) influx evoked by KCl depolarization. Docking studies show that compounds 16 and 18 adopted different orientations and conformations inside the active-site gorges of hAChE and hBuChE. The structural and energetic features of the 16-AChE and 18-AChE complexes compared to the 16-BuChE and 18-BuChE complexes account for a higher affinity of the ligand toward AChE. The present data indicate that compounds 2, 7, 17, 18, and 36 may represent attractive multipotent molecules for the potential treatment of Alzheimer's disease.
authors: Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculty of Pharmacy, University of Lisbon, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal.
authors: Daniel
authors: D
authors: Silva
authors: Mourad
authors: M
authors: Chioua
authors: Abdelouahid
authors: A
authors: Samadi
authors: Paula
authors: P
authors: Agostinho
authors: Pedro
authors: P
authors: Garção
authors: Rocío
authors: R
authors: Lajarín-Cuesta
authors: Cristobal
authors: C
authors: de Los Ríos
authors: Isabel
authors: I
authors: Iriepa
authors: Ignacio
authors: I
authors: Moraleda
authors: Laura
authors: L
authors: Gonzalez-Lafuente
authors: Eduarda
authors: E
authors: Mendes
authors: Concepción
authors: C
authors: Pérez
authors: María Isabel
authors: MI
authors: Rodríguez-Franco
authors: José
authors: J
authors: Marco-Contelles
authors: M
authors: M
authors: Carmo Carreiras
mesh_terms: D016229:Amyloid beta-Peptides / Q000633:toxicity*; D002091:Butyrylcholinesterase / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008958:Models, Molecular; D010446:Peptide Fragments / Q000633:toxicity*
chemical_list: D016229:Amyloid beta-Peptides; D002800:Cholinesterase Inhibitors; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D002091:Butyrylcholinesterase
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