{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T19:18:14Z","timestamp":1777403894484,"version":"3.51.4"},"reference-count":126,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,8,9]],"date-time":"2023-08-09T00:00:00Z","timestamp":1691539200000},"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","id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002261","name":"Russian Foundation for Basic Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002261","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>We investigated the inhibitory activities of novel 9-phosphoryl-9,10-dihydroacridines and 9-phosphorylacridines against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and carboxylesterase (CES). We also studied the abilities of the new compounds to interfere with the self-aggregation of \u03b2-amyloid (A\u03b2<jats:sub>42<\/jats:sub>) in the thioflavin test as well as their antioxidant activities in the ABTS and FRAP assays. We used molecular docking, molecular dynamics simulations, and quantum-chemical calculations to explain experimental results. All new compounds weakly inhibited AChE and off-target CES. Dihydroacridines with aryl substituents in the phosphoryl moiety inhibited BChE; the most active were the dibenzyloxy derivative <jats:bold>1d<\/jats:bold> and its diphenethyl bioisostere <jats:bold>1e<\/jats:bold> (IC<jats:sub>50<\/jats:sub> = 2.90 \u00b1 0.23\u00a0\u00b5M and 3.22 \u00b1 0.25\u00a0\u00b5M, respectively). Only one acridine, <jats:bold>2d<\/jats:bold>, an analog of dihydroacridine, <jats:bold>1d<\/jats:bold>, was an effective BChE inhibitor (IC<jats:sub>50<\/jats:sub> = 6.90 \u00b1 0.55\u00a0\u03bcM), consistent with docking results. Dihydroacridines inhibited A\u03b2<jats:sub>42<\/jats:sub> self-aggregation; <jats:bold>1d<\/jats:bold> and <jats:bold>1e<\/jats:bold> were the most active (58.9% \u00b1 4.7% and 46.9% \u00b1 4.2%, respectively). All dihydroacridines <jats:bold>1<\/jats:bold> demonstrated high ABTS<jats:sup>\u2022+<\/jats:sup>-scavenging and iron-reducing activities comparable to Trolox, but acridines <jats:bold>2<\/jats:bold> were almost inactive. Observed features were well explained by quantum-chemical calculations. ADMET parameters calculated for all compounds predicted favorable intestinal absorption, good blood\u2013brain barrier permeability, and low cardiac toxicity. Overall, the best results were obtained for two dihydroacridine derivatives <jats:bold>1d<\/jats:bold> and <jats:bold>1e<\/jats:bold> with dibenzyloxy and diphenethyl substituents in the phosphoryl moiety. These compounds displayed high inhibition of BChE activity and A\u03b2<jats:sub>42<\/jats:sub> self-aggregation, high antioxidant activity, and favorable predicted ADMET profiles. Therefore, we consider <jats:bold>1d<\/jats:bold> and <jats:bold>1e<\/jats:bold> as lead compounds for further in-depth studies as potential anti-AD preparations.<\/jats:p>","DOI":"10.3389\/fphar.2023.1219980","type":"journal-article","created":{"date-parts":[[2023,8,9]],"date-time":"2023-08-09T07:31:25Z","timestamp":1691566285000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["Derivatives of 9-phosphorylated acridine as butyrylcholinesterase inhibitors with antioxidant activity and the ability to inhibit \u03b2-amyloid self-aggregation: potential therapeutic agents for Alzheimer\u2019s disease"],"prefix":"10.3389","volume":"14","author":[{"given":"Galina F.","family":"Makhaeva","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nadezhda V.","family":"Kovaleva","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elena V.","family":"Rudakova","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Natalia P.","family":"Boltneva","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sofya V.","family":"Lushchekina","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tatiana Yu","family":"Astakhova","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elena N.","family":"Timokhina","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Olga G.","family":"Serebryakova","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander V.","family":"Shchepochkin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maxim A.","family":"Averkov","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Irina A.","family":"Utepova","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nadezhda S.","family":"Demina","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eugene V.","family":"Radchenko","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vladimir A.","family":"Palyulin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vladimir P.","family":"Fisenko","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sergey O.","family":"Bachurin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Oleg N.","family":"Chupakhin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valery N.","family":"Charushin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rudy J.","family":"Richardson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2023,8,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"6158","DOI":"10.1063\/1.478522","article-title":"Toward reliable density functional methods without adjustable parameters: The PBE0 model","volume":"110","author":"Adamo","year":"1999","journal-title":"J. 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