Novel Acetylcholinesterase Inhibitors Based on Uracil Moiety for Possible Treatment of Alzheimer Disease

• Published in: Molecules (Basel, Switzerland) Switzerland), 2020-09, Vol.25 (18), p.4191
• Main Authors: Semenov, Vyacheslav E, Zueva, Irina V, Mukhamedyarov, Marat A, Lushchekina, Sofya V, Petukhova, Elena O, Gubaidullina, Lilya M, Krylova, Evgeniya S, Saifina, Lilya F, Lenina, Oksana A, Petrov, Konstantin A
• Format: Article
• Language: English
• Subjects: 6-methyluracil; Acetylcholinesterase; Acetylcholinesterase - chemistry; Alzheimer disease; Alzheimer Disease - drug therapy; Alzheimer's disease; Ammonium; Ammonium Compounds - chemistry; Animal diseases; Animal models; Animals; Anions; Apoptosis; Behavior, Animal; Binding Sites; Blood-Brain Barrier - drug effects; Butyrylcholinesterase - chemistry; Catalytic Domain; Chains; Cholinesterase Inhibitors - pharmacology; Cognition & reasoning; Disease Models, Animal; Drug Design; Drug Evaluation, Preclinical; Enzymes; Humans; Inhibitors; Inhibitory Concentration 50; Maze Learning; Medical treatment; Memory; Memory Disorders - drug therapy; Mice; Molecular chains; Molecular Docking Simulation; Molecular modelling; peripheral anionic site; Scopolamine; Selectivity; Transgenic animals; Uracil; Uracil - analogs & derivatives; Uracil - chemistry
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules25184191

In this study, novel derivatives based on 6-methyluracil and condensed uracil were synthesized, namely, 2,4-quinazoline-2,4-dione with ω-( -nitrilebenzylethylamino) alkyl chains at the N atoms of the pyrimidine ring. In this series of synthesized compounds, the polymethylene chains were varied from having tetra- to hexamethylene chains, and secondary NH, tertiary ethylamino, and quaternary ammonium groups were introduced into the chains. The molecular modeling of the compounds indicated that they could function as dual binding site acetylcholinesterase inhibitors, binding to both the peripheral anionic site and active site. The data from in vitro experiments show that the most active compounds exhibit affinity toward acetylcholinesterase within a nanomolar range, with selectivity for acetylcholinesterase over butyrylcholinesterase reaching four orders of magnitude. In vivo biological assays demonstrated the potency of these compounds in the treatment of memory impairment using an animal model of Alzheimer disease.