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© 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

Abstract

A series of bisuracils, in which uracil and 3,6-dimethyluracil moieties were bridged with a polymethylene spacer, and the uracil moiety contained a pentamethylene radical with ionic and non-ionic aminobenzyl groups, were synthesised. These bisuracils have been identified as cholinesterase inhibitors with exceptional selectivity for acetylcholinesterase (AChE) over butyrylcholinesterase (BuChE). These bisuracils, which have been identified as highly effective AChE inhibitors, demonstrated activity at nano- and sub-nanomolar concentrations, with exceptional selectivity for AChE over BuChE. In kinetic studies of lead bisuracils 2b and 3c, both compounds exhibited mixed-type inhibition against AChE and BuChE. Additionally, molecular dynamic simulations demonstrated robust and stable interactions of 2b and 3c with the binding sites of their target. Bisuracil 2b showed significant potential for protection of AChE from irreversible inhibition by paraoxon; the most effective dose of 0.01 mg/kg was shown to reduce mortality in paraoxon-poisoned mice. Bisuracil 3c effectively inhibited brain AChE activity, reversing scopolamine-induced amnesia in mice at a dose of 5 mg/kg, which indicates its potential for cognitive enhancement. These findings position ionic bisuracils as promising prophylactics against organophosphate poisoning and non-ionic bisuracils as viable candidates for Alzheimer’s disease therapeutics.

Details

Title
Ionic and Non-Ionic Counterparts Based on Bis(Uracilyl)Alkane Moiety with Highest Selectivity Towards Acetylcholinesterase for Protection Against Organophosphate Poisoning and Treating Alzheimer’s Disease
Author
Zueva, Irina V 1   VIAFID ORCID Logo  ; Saifina, Liliya F 1   VIAFID ORCID Logo  ; Gubaidullina, Liliya M 1 ; Shulaeva, Marina M 1   VIAFID ORCID Logo  ; Kharlamova, Alexandra D 1 ; Lenina, Oksana A 1   VIAFID ORCID Logo  ; Belyaev, Grigory P 1   VIAFID ORCID Logo  ; Ziganshina, Albina Y 1   VIAFID ORCID Logo  ; Gao, Shan 2 ; Tang, Wenjian 2 ; Semenov, Vyacheslav E 1   VIAFID ORCID Logo  ; Petrov, Konstantin A 3 

 Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center of RAS Arbuzov str., 8, Kazan 420088, [email protected] (L.F.S.); [email protected] (L.M.G.); [email protected] (M.M.S.); [email protected] (A.D.K.); [email protected] (O.A.L.); [email protected] (G.P.B.); [email protected] (A.Y.Z.); [email protected] (K.A.P.) 
 School of Pharmacy, Anhui Medical University, Hefei 230032, China; [email protected] 
 Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center of RAS Arbuzov str., 8, Kazan 420088, [email protected] (L.F.S.); [email protected] (L.M.G.); [email protected] (M.M.S.); [email protected] (A.D.K.); [email protected] (O.A.L.); [email protected] (G.P.B.); [email protected] (A.Y.Z.); [email protected] (K.A.P.), Graduate School of Biology, Institute of Fundamental Medicine and Biology, Kazan Federal University, 18 Kremlyovskaya str, Kazan 420008, Russia 
First page
3759
Publication year
2025
Publication date
2025
Publisher
MDPI AG
ISSN
16616596
e-ISSN
14220067
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
3194614543
Copyright
© 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.