Conjugates of γ-Carbolines and Phenothiazine as new selective inhibitors of butyrylcholinesterase and blockers of NMDA receptors for Alzheimer Disease.
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.
Institute of Physiologically Active Compounds Russian Academy of Sciences, Chernogolovka, 142432, Russia.
Galina F
GF
Makhaeva
1] Institute of Physiologically Active Compounds Russian Academy of Sciences, Chernogolovka, 142432, Russia [2] Emanuel Institute of Biochemical Physics, Russian Academy of Sciences, Moscow, 119334, Russia.
Sofya V
SV
Lushchekina
Institute of Physiologically Active Compounds Russian Academy of Sciences, Chernogolovka, 142432, Russia.
Natalia P
NP
Boltneva
Institute of Physiologically Active Compounds Russian Academy of Sciences, Chernogolovka, 142432, Russia.
Vladimir B
VB
Sokolov
Institute of Physiologically Active Compounds Russian Academy of Sciences, Chernogolovka, 142432, Russia.
Vladimir V
VV
Grigoriev
Institute of Physiologically Active Compounds Russian Academy of Sciences, Chernogolovka, 142432, Russia.
Olga G
OG
Serebryakova
Institute of Physiologically Active Compounds Russian Academy of Sciences, Chernogolovka, 142432, Russia.
Ekaterina A
EA
Vikhareva
Institute of Physiologically Active Compounds Russian Academy of Sciences, Chernogolovka, 142432, Russia.
Alexey Yu
AY
Aksinenko
1] Departamento de Nutrición y Bioquímica, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá D.C., Colombia [2] Instituto de Ciencias Biomédicas, Universidad Autónoma de Chile, Santiago, Chile.
George E
GE
Barreto
1] GALLY International Biomedical Research Consulting LLC., San Antonio, TX 78229, USA [2] School of Health Science and Healthcare Administration, University of Atlanta, Johns Creek, GA 30097, USA.
Gjumrakch
G
Aliev
Institute of Physiologically Active Compounds Russian Academy of Sciences, Chernogolovka, 142432, Russia.
Sergey O
SO
Bachurin
D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D002091:Butyrylcholinesterase / Q000737:chemistry* / Q000378:metabolism; D002243:Carbolines / Q000008:administration & dosage / Q000737:chemistry*; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D015195:Drug Design; D004789:Enzyme Activation; D006801:Humans; D008956:Models, Chemical; D062105:Molecular Docking Simulation; D010640:Phenothiazines / Q000008:administration & dosage / Q000737:chemistry*; D011485:Protein Binding; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome
D002243:Carbolines; D002800:Cholinesterase Inhibitors; D004338:Drug Combinations; D010640:Phenothiazines; D016194:Receptors, N-Methyl-D-Aspartate; C055572:gamma-carboline; D002091:Butyrylcholinesterase; C031637:phenothiazine