{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T12:28:10Z","timestamp":1785414490101,"version":"3.56.0"},"reference-count":54,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T00:00:00Z","timestamp":1778198400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Medical University of Bialystok","award":["B.SUB.26.311"],"award-info":[{"award-number":["B.SUB.26.311"]}]},{"award":["B.SUB.26.311"],"award-info":[{"award-number":["B.SUB.26.311"]}],"id":[{"id":"https:\/\/ror.org\/00y4ya841","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>A novel series of hybrid tetrahydro-\u03b2-carboline (TH\u03b2C)-imidazolium (IM) salts incorporating a fused diketopiperazine scaffold was designed, synthesized, and evaluated as cholinesterase inhibitors for potential application in Alzheimer\u2019s disease. The molecular design integrates a \u03c0-conjugated TH\u03b2C core with a cationic IM moiety to promote dual-site interactions within the acetylcholinesterase (AChE) active-site gorge. All compounds exhibited micromolar inhibitory activity against AChE and butyrylcholinesterase (BChE), with a pronounced preference for AChE. The most active derivative, 12d, showed an IC50 value of 0.72 \u03bcM toward AChE, while compound 12c demonstrated the highest selectivity (SI = 8.4). Structure\u2013activity relationship studies revealed that both stereochemistry and N-alkyl chain length are critical determinants of activity, with S,S-configured derivatives consistently outperforming their R,R-configured analogs. In silico ADMET analysis indicated favorable physicochemical properties and predicted central nervous system permeability, although potential hepatotoxicity highlights the need for further optimization. Molecular docking studies suggested that the most promising compound adopts a dual-binding mode, interacting with both the peripheral anionic site and catalytic active site of AChE. These results identify TH\u03b2C-IM hybrids as a structurally novel and promising scaffold for the development of selective cholinesterase inhibitors, providing a basis for further optimization toward multifunctional anti-Alzheimer agents.<\/jats:p>","DOI":"10.3390\/molecules31101563","type":"journal-article","created":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T19:35:43Z","timestamp":1778528143000},"page":"1563","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Design, Synthesis, and Biological Evaluation of Highly Functionalized Tetrahydro-\u03b2-carboline-imidazolium Hybrids Targeting Cholinesterases"],"prefix":"10.3390","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1183-054X","authenticated-orcid":false,"given":"Agnieszka","family":"Hryniewicka","sequence":"first","affiliation":[{"name":"Department of Organic Chemistry, Faculty of Medicine, Division of Dentistry and Division of Medical Education in English, Medical University of Bialystok, Mickiewicza 2A, 15-222 Bialystok, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Damian","family":"Pawelski","sequence":"additional","affiliation":[{"name":"Department of Organic Chemistry, Faculty of Medicine, Division of Dentistry and Division of Medical Education in English, Medical University of Bialystok, Mickiewicza 2A, 15-222 Bialystok, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0538-6059","authenticated-orcid":false,"given":"Marta Eliza","family":"Plonska-Brzezinska","sequence":"additional","affiliation":[{"name":"Department of Organic Chemistry, Faculty of Medicine, Division of Dentistry and Division of Medical Education in English, Medical University of Bialystok, Mickiewicza 2A, 15-222 Bialystok, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"15056","DOI":"10.1038\/nrdp.2015.56","article-title":"Alzheimer\u2019s Disease","volume":"1","author":"Masters","year":"2015","journal-title":"Nat. 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