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The development of new effective therapeutic agents for AD is one of the most urgent and challenging tasks. To address this need, we used an aminoalkylene linker to combine the well-known anticholinesterase drug tacrine with antioxidant 2-tolylhydrazinylidene-1,3-diketones to create 3 groups of hybrid compounds as new multifunctional agents with the potential for AD treatment. Lead compounds of the new conjugates effectively inhibited acetylcholinesterase (AChE, IC50 0.24\u20130.34 \u00b5M) and butyrylcholinesterase (BChE, IC50 0.036\u20130.0745 \u00b5M), with weak inhibition of off-target carboxylesterase. Anti-AChE activity increased with elongation of the alkylene spacer, in agreement with molecular docking, which showed compounds binding to both the catalytic active site and peripheral anionic site (PAS) of AChE, consistent with mixed type reversible inhibition. PAS binding along with effective propidium displacement suggest the potential of the hybrids to block AChE-induced \u03b2-amyloid aggregation, a disease-modifying effect. All of the conjugates demonstrated metal chelating ability for Cu2+, Fe2+, and Zn2+, as well as high antiradical activity in the ABTS test. Non-fluorinated hybrid compounds 6 and 7 also showed Fe3+ reducing activity in the FRAP test. Predicted ADMET and physicochemical properties of conjugates indicated good CNS bioavailability and safety parameters acceptable for potential lead compounds at the early stages of anti-AD drug development.<\/jats:p>","DOI":"10.3390\/biom12111551","type":"journal-article","created":{"date-parts":[[2022,10,24]],"date-time":"2022-10-24T10:09:23Z","timestamp":1666606163000},"page":"1551","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["New Multifunctional Agents for Potential Alzheimer\u2019s Disease Treatment Based on Tacrine Conjugates with 2-Arylhydrazinylidene-1,3-Diketones"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7365-8108","authenticated-orcid":false,"given":"Natalia A.","family":"Elkina","sequence":"first","affiliation":[{"name":"Postovsky Institute of Organic Synthesis, Urals Branch of Russian Academy of Sciences, Yekaterinburg 620990, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria V.","family":"Grishchenko","sequence":"additional","affiliation":[{"name":"Postovsky Institute of Organic Synthesis, Urals Branch of Russian Academy of Sciences, Yekaterinburg 620990, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6611-2855","authenticated-orcid":false,"given":"Evgeny V.","family":"Shchegolkov","sequence":"additional","affiliation":[{"name":"Postovsky Institute of Organic Synthesis, Urals Branch of Russian Academy of Sciences, Yekaterinburg 620990, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8136-6906","authenticated-orcid":false,"given":"Galina F.","family":"Makhaeva","sequence":"additional","affiliation":[{"name":"Institute of Physiologically Active Compounds at Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, Chernogolovka 142432, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4990-5068","authenticated-orcid":false,"given":"Nadezhda V.","family":"Kovaleva","sequence":"additional","affiliation":[{"name":"Institute of Physiologically Active Compounds at Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, Chernogolovka 142432, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elena V.","family":"Rudakova","sequence":"additional","affiliation":[{"name":"Institute of Physiologically Active Compounds at Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, Chernogolovka 142432, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7171-8832","authenticated-orcid":false,"given":"Natalia P.","family":"Boltneva","sequence":"additional","affiliation":[{"name":"Institute of Physiologically Active Compounds at Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, Chernogolovka 142432, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6922-020X","authenticated-orcid":false,"given":"Sofya V.","family":"Lushchekina","sequence":"additional","affiliation":[{"name":"Institute of Physiologically Active Compounds at Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, Chernogolovka 142432, Russia"},{"name":"Emanuel Institute of Biochemical Physics Russian Academy of Sciences, Moscow 119334, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tatiana Y.","family":"Astakhova","sequence":"additional","affiliation":[{"name":"Emanuel Institute of Biochemical Physics Russian Academy of Sciences, Moscow 119334, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2091-7022","authenticated-orcid":false,"given":"Eugene V.","family":"Radchenko","sequence":"additional","affiliation":[{"name":"Institute of Physiologically Active Compounds at Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, Chernogolovka 142432, Russia"},{"name":"Department of Chemistry, Lomonosov Moscow State University, Moscow 119991, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8792-8386","authenticated-orcid":false,"given":"Vladimir A.","family":"Palyulin","sequence":"additional","affiliation":[{"name":"Institute of Physiologically Active Compounds at Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, Chernogolovka 142432, Russia"},{"name":"Department of Chemistry, Lomonosov Moscow State University, Moscow 119991, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ekaterina F.","family":"Zhilina","sequence":"additional","affiliation":[{"name":"Postovsky Institute of Organic Synthesis, Urals Branch of Russian Academy of Sciences, Yekaterinburg 620990, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anastasiya N.","family":"Perminova","sequence":"additional","affiliation":[{"name":"Postovsky Institute of Organic Synthesis, Urals Branch of Russian Academy of Sciences, Yekaterinburg 620990, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luka S.","family":"Lapshin","sequence":"additional","affiliation":[{"name":"Postovsky Institute of Organic Synthesis, Urals Branch of Russian Academy of Sciences, Yekaterinburg 620990, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yanina V.","family":"Burgart","sequence":"additional","affiliation":[{"name":"Postovsky Institute of Organic 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Engineering, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"(2020). 2020 Alzheimer\u2019s disease facts and figures. 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