| Autor: |
Semenov VE; Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center of RAS, Arbuzov str. 8, 420088 Kazan, Russia., Zueva IV; Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center of RAS, Arbuzov str. 8, 420088 Kazan, Russia., Mukhamedyarov MA; Institute of Neuroscience, Kazan State Medical University, 420012 Kazan, Russia., Lushchekina SV; Emanuel Institute of Biochemical Physics, Kosygina st. 4, 119334 Moscow, Russia., Petukhova EO; Institute of Neuroscience, Kazan State Medical University, 420012 Kazan, Russia., Gubaidullina LM; Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center of RAS, Arbuzov str. 8, 420088 Kazan, Russia., Krylova ES; Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center of RAS, Arbuzov str. 8, 420088 Kazan, Russia., Saifina LF; Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center of RAS, Arbuzov str. 8, 420088 Kazan, Russia., Lenina OA; Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center of RAS, Arbuzov str. 8, 420088 Kazan, Russia., Petrov KA; Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center of RAS, Arbuzov str. 8, 420088 Kazan, Russia.; Institute of Fundamental Medicine and Biology, Kazan Federal University, Kremlyovskaya str., 18, 420008 Kazan, Russia. |
| Abstrakt: |
In this study, novel derivatives based on 6-methyluracil and condensed uracil were synthesized, namely, 2,4-quinazoline-2,4-dione with ω-( ortho -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. |
