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The hybrids exhibited broad-spectrum biological activity. All new conjugates were potent inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with selectivity toward BChE. The structure of the salicylamide moiety exerted little effect on anticholinesterase activity, but AChE inhibition increased with spacer elongation. The most active conjugates were salicylimine derivatives: IC50 values of the lead compound 10c were 0.0826 \u00b5M (AChE) and 0.0156 \u00b5M (BChE), with weak inhibition of the off-target carboxylesterase. The hybrids were mixed-type reversible inhibitors of both cholinesterases and displayed dual binding to the catalytic and peripheral anionic sites of AChE in molecular docking, which, along with experimental results on propidium iodide displacement, suggested their potential to block AChE-induced \u03b2-amyloid aggregation. All conjugates inhibited A\u03b242 self-aggregation in the thioflavin test, and inhibition increased with spacer elongation. Salicylimine 10c and salicylamide 5c with (CH2)8 spacers were the lead compounds for inhibiting A\u03b242 self-aggregation, which was corroborated by molecular docking to A\u03b242. ABTS\u2022+-scavenging activity was highest for salicylamides 5a\u2013c, intermediate for salicylimines 10a\u2013c, low for F-containing salicylamides 7, and non-existent for methoxybenzoylamides 6 and difluoromethoxybenzoylamides 8. In the FRAP antioxidant (AO) assay, the test compounds displayed little or no activity. Quantum chemical analysis and molecular dynamics (MD) simulations with QM\/MM potentials explained the AO structure\u2013activity relationships. All conjugates were effective chelators of Cu2+, Fe2+, and Zn2+, with molar compound\/metal (Cu2+) ratios of 2:1 (5b) and ~1:1 (10b). Conjugates exerted comparable or lower cytotoxicity than tacrine on mouse hepatocytes and had favorable predicted intestinal absorption and blood-brain barrier permeability. The overall results indicate that the synthesized conjugates are promising new multifunctional agents for the potential treatment of AD.<\/jats:p>","DOI":"10.3390\/ijms24032285","type":"journal-article","created":{"date-parts":[[2023,1,25]],"date-time":"2023-01-25T03:53:18Z","timestamp":1674618798000},"page":"2285","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["Conjugates of Tacrine and Salicylic Acid Derivatives as New Promising Multitarget Agents for Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8136-6906","authenticated-orcid":false,"given":"Galina F.","family":"Makhaeva","sequence":"first","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":[{"vocabulary":"crossref","role":"author"}]},{"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":[{"vocabulary":"crossref","role":"author"}]},{"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":[{"vocabulary":"crossref","role":"author"}]},{"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":[{"vocabulary":"crossref","role":"author"}]},{"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":[{"vocabulary":"crossref","role":"author"}]},{"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":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatiana Y.","family":"Astakhova","sequence":"additional","affiliation":[{"name":"Emanuel Institute of Biochemical Physics Russian Academy of Sciences, Moscow 119334, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga G.","family":"Serebryakova","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":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena N.","family":"Timokhina","sequence":"additional","affiliation":[{"name":"Emanuel Institute of Biochemical Physics Russian Academy of Sciences, Moscow 119334, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"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":[{"vocabulary":"crossref","role":"author"}]},{"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":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariya V.","family":"Ulitko","sequence":"additional","affiliation":[{"name":"Institute of Natural Sciences and Mathematics of the Ural Federal University Named after the First President of Russia B. 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