{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:11:11Z","timestamp":1760058671439,"version":"build-2065373602"},"reference-count":39,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,4,16]],"date-time":"2025-04-16T00:00:00Z","timestamp":1744761600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006769","name":"Russian Science Foundation","doi-asserted-by":"publisher","award":["24-75-10086"],"award-info":[{"award-number":["24-75-10086"]}],"id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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\u2019s disease therapeutics.<\/jats:p>","DOI":"10.3390\/ijms26083759","type":"journal-article","created":{"date-parts":[[2025,4,16]],"date-time":"2025-04-16T08:09:17Z","timestamp":1744790957000},"page":"3759","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"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\u2019s Disease"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0518-0384","authenticated-orcid":false,"given":"Irina V.","family":"Zueva","sequence":"first","affiliation":[{"name":"Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center of RAS Arbuzov str., 8, Kazan 420088, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7504-1331","authenticated-orcid":false,"given":"Liliya F.","family":"Saifina","sequence":"additional","affiliation":[{"name":"Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center of RAS Arbuzov str., 8, Kazan 420088, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liliya M.","family":"Gubaidullina","sequence":"additional","affiliation":[{"name":"Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center of RAS Arbuzov str., 8, Kazan 420088, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6014-0177","authenticated-orcid":false,"given":"Marina M.","family":"Shulaeva","sequence":"additional","affiliation":[{"name":"Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center of RAS Arbuzov str., 8, Kazan 420088, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexandra D.","family":"Kharlamova","sequence":"additional","affiliation":[{"name":"Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center of RAS Arbuzov str., 8, Kazan 420088, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3831-7367","authenticated-orcid":false,"given":"Oksana A.","family":"Lenina","sequence":"additional","affiliation":[{"name":"Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center of RAS Arbuzov str., 8, Kazan 420088, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3157-3402","authenticated-orcid":false,"given":"Grigory P.","family":"Belyaev","sequence":"additional","affiliation":[{"name":"Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center of RAS Arbuzov str., 8, Kazan 420088, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4507-9923","authenticated-orcid":false,"given":"Albina Y.","family":"Ziganshina","sequence":"additional","affiliation":[{"name":"Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center of RAS Arbuzov str., 8, Kazan 420088, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shan","family":"Gao","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Anhui Medical University, Hefei 230032, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenjian","family":"Tang","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Anhui Medical University, Hefei 230032, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8350-2433","authenticated-orcid":false,"given":"Vyacheslav E.","family":"Semenov","sequence":"additional","affiliation":[{"name":"Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center of RAS Arbuzov str., 8, Kazan 420088, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Konstantin A.","family":"Petrov","sequence":"additional","affiliation":[{"name":"Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center of RAS Arbuzov str., 8, Kazan 420088, Russia"},{"name":"Graduate School of Biology, Institute of Fundamental Medicine and Biology, Kazan Federal University, 18 Kremlyovskaya str, Kazan 420008, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"315","DOI":"10.2174\/1570159X11311030006","article-title":"Acetylcholinesterase Inhibitors: Pharmacology and toxicology","volume":"11","author":"Colovic","year":"2013","journal-title":"Curr. 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