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Conjugates of γ-Carbolines and Phenothiazine as new selective inhibitors of butyrylcholinesterase and blockers of NMDA receptors for Alzheimer Disease.

Abstract
Alzheimer disease is a multifactorial pathology and the development of new multitarget neuroprotective drugs is promising and attractive. We synthesized a group of original compounds, which combine in one molecule γ-carboline fragment of dimebon and phenothiazine core of methylene blue (MB) linked by 1-oxo- and 2-hydroxypropylene spacers. Inhibitory activity of the conjugates toward acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and structurally close to them carboxylesterase (CaE), as well their binding to NMDA-receptors were evaluated in vitro and in silico. These newly synthesized compounds showed significantly higher inhibitory activity toward BChE with IC50 values in submicromolar and micromolar range and exhibited selective inhibitory action against BChE over AChE and CaE. Kinetic studies for the 9 most active compounds indicated that majority of them were mixed-type BChE inhibitors. The main specific protein-ligand interaction is π-π stacking of phenothiazine ring with indole group of Trp82. These compounds emerge as promising safe multitarget ligands for the further development of a therapeutic approach against aging-related neurodegenerative disorders such as Alzheimer and/or other pathological conditions.
AuthorsGalina F Makhaeva, Sofya V Lushchekina, Natalia P Boltneva, Vladimir B Sokolov, Vladimir V Grigoriev, Olga G Serebryakova, Ekaterina A Vikhareva, Alexey Yu Aksinenko, George E Barreto, Gjumrakch Aliev, Sergey O Bachurin
JournalScientific reports (Sci Rep) Vol. 5 Pg. 13164 (Aug 18 2015) ISSN: 2045-2322 [Electronic] England
PMID26281952 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Carbolines
  • Cholinesterase Inhibitors
  • Drug Combinations
  • Phenothiazines
  • Receptors, N-Methyl-D-Aspartate
  • gamma-carboline
  • Butyrylcholinesterase
  • phenothiazine
Topics
  • Alzheimer Disease (drug therapy, metabolism)
  • Animals
  • Binding Sites
  • Butyrylcholinesterase (chemistry, metabolism)
  • Carbolines (administration & dosage, chemistry)
  • Cholinesterase Inhibitors (administration & dosage, chemistry)
  • Dose-Response Relationship, Drug
  • Drug Combinations
  • Drug Design
  • Enzyme Activation
  • Humans
  • Models, Chemical
  • Molecular Docking Simulation
  • Phenothiazines (administration & dosage, chemistry)
  • Protein Binding
  • Receptors, N-Methyl-D-Aspartate (antagonists & inhibitors)
  • Treatment Outcome

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