Synthesis, pharmacological assessment, and molecular modeling of acetylcholinesterase/butyrylcholinesterase inhibitors: Effect against amyloid-β-induced neurotoxicity

Daniel Silva, Mourad Chioua, Abdelouahid Samadi, Paula Agostinho, Pedro Garção, Rocío Lajarín-Cuesta, Cristobal De Los Ríos, Isabel Iriepa, Ignacio Moraleda, Laura Gonzalez-Lafuente, Eduarda Mendes, Concepción Pérez, María Isabel Rodríguez-Franco, José Marco-Contelles, M. Carmo Carreiras

Research output: Contribution to journalArticlepeer-review

38 Citations (Scopus)

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) [IC50 (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) [IC50 (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 Aβ1-42. All compounds were effective in preventing the enhancement of AChE activity induced by Aβ1-42. 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 Aβ1-42. Compounds 2, 7, 12, 13, 17, 18, and 36 may act as antagonists of voltage sensitive calcium channels, since they significantly prevented the Ca2+ 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.

Original languageEnglish
Pages (from-to)547-565
Number of pages19
JournalACS Chemical Neuroscience
Volume4
Issue number4
DOIs
Publication statusPublished - Apr 17 2013
Externally publishedYes

Keywords

  • AChE/BuChE inhibitors
  • Alzheimer's disease
  • Aβ peptide
  • Ca dyshomeostasis
  • Pyridonepezils
  • neuroprotection
  • quinolinodonepezils

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Cognitive Neuroscience
  • Cell Biology

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