{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T22:44:43Z","timestamp":1768949083142,"version":"3.49.0"},"reference-count":75,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T00:00:00Z","timestamp":1768867200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Polish Ministry of Education and Science"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>A series of novel granatane\u2013triazole hybrid molecules was designed, synthesized, and evaluated as dual acetylcholinesterase (AChE) and \u03b2-secretase 1 (BACE1) inhibitors. The compounds were obtained through a convergent synthetic route involving azide formation, triazole construction via dipolar cycloaddition, and final coupling with a granatane scaffold to give a pseudopelletierine (3-granatanone) analogue. In vitro assays demonstrated that all target compounds inhibited both AChE and BACE1. Molecular docking and molecular dynamics simulations revealed stable interactions with key catalytic residues, suggesting distinct binding modes compared to reference ligands. QSAR-based pharmacokinetic predictions indicated favorable blood\u2013brain barrier permeability and compliance with key drug-likeness filters. These findings identify granatane\u2013triazole hybrids as promising multi-target directed ligand (MTDL) candidates with potential for further optimization in the search for new anti-Alzheimer therapeutics.<\/jats:p>","DOI":"10.3390\/ijms27021008","type":"journal-article","created":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T09:24:34Z","timestamp":1768901074000},"page":"1008","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Design, Synthesis, and Biological Evaluation of Novel Acetylcholinesterase and \u03b2-Secretase 1 Inhibitors"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3479-0480","authenticated-orcid":false,"given":"Danuta","family":"Drozdowska","sequence":"first","affiliation":[{"name":"Department of Organic Chemistry, Medical University of Bialystok, 15-222 Bialystok, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3878-8588","authenticated-orcid":false,"given":"Damian","family":"Pawelski","sequence":"additional","affiliation":[{"name":"Department of Organic Chemistry, Medical University of Bialystok, 15-222 Bialystok, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4493-1547","authenticated-orcid":false,"given":"Agnieszka","family":"Wr\u00f3bel-Ta\u0142a\u0142aj","sequence":"additional","affiliation":[{"name":"Department of Organic Chemistry, Medical University of Bialystok, 15-222 Bialystok, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0538-6059","authenticated-orcid":false,"given":"Marta","family":"Plonska-Brzezinska","sequence":"additional","affiliation":[{"name":"Department of Organic Chemistry, Medical University of Bialystok, 15-222 Bialystok, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4581-947X","authenticated-orcid":false,"given":"Beata","family":"Kolesinska","sequence":"additional","affiliation":[{"name":"Institute of Organic Chemistry, Lodz University of Technology, 90-924 Lodz, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2358-0960","authenticated-orcid":false,"given":"Ryszard","family":"Lazny","sequence":"additional","affiliation":[{"name":"Department of Polymers and Organic Synthesis, Faculty of Chemistry, University of Bialystok, 15-245 Bialystok, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2157-4180","authenticated-orcid":false,"given":"Barbara","family":"Seroka","sequence":"additional","affiliation":[{"name":"Department of Polymers and Organic Synthesis, Faculty of Chemistry, University of Bialystok, 15-245 Bialystok, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-6756-3350","authenticated-orcid":false,"given":"Cezary","family":"Parzych","sequence":"additional","affiliation":[{"name":"Department of Physical Chemistry, Faculty of Chemistry, University of Bialystok, 15-245 Bialystok, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1657-1871","authenticated-orcid":false,"given":"Artur","family":"Ratkiewicz","sequence":"additional","affiliation":[{"name":"Department of Physical Chemistry, Faculty of Chemistry, University of Bialystok, 15-245 Bialystok, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"5148","DOI":"10.1021\/acsomega.4c05527","article-title":"Newer Therapeutic Approaches in Treating Alzheimer\u2019s Disease: A Comprehensive Review","volume":"10","author":"Kalyan","year":"2025","journal-title":"ACS Omega"},{"key":"ref_2","first-page":"22","article-title":"Multitarget Drug Discovery: A New Paradigm in Pharmaceutical Research","volume":"7","author":"Lyar","year":"2023","journal-title":"J. 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