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The compounds featured variations in alkyl linker length that connects coumarin and triazole and substitution at the 5-position of the isatin ring. Several derivatives showed potent butyrylcholinesterase (BChE) inhibition with selectivity over acetylcholinesterase (AChE). The lead compound, 6c1, exhibited strong BChE inhibition (IC50 = 1.74 \u03bcM), surpassing donepezil. Enzyme kinetics revealed a mixed-type mechanism, while molecular docking studies confirmed dual binding at catalytic and peripheral sites. Structure\u2013activity relationship (SAR) analysis highlighted the influence of linker flexibility and steric\/electronic effects of substituents. The observed BChE selectivity, combined with favorable in vitro profiles, identifies these hybrids as promising leads for AD drug development.<\/jats:p>","DOI":"10.3390\/molecules30102121","type":"journal-article","created":{"date-parts":[[2025,5,12]],"date-time":"2025-05-12T06:17:08Z","timestamp":1747030628000},"page":"2121","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Synthesis, Biological Evaluation, and Molecular Docking Studies of Novel Coumarin\u2013Triazole\u2013Isatin Hybrids as Selective Butyrylcholinesterase Inhibitors"],"prefix":"10.3390","volume":"30","author":[{"given":"Aleksandar","family":"Dimkovski","sequence":"first","affiliation":[{"name":"Institute for Pharmaceutical Chemistry, Faculty of Pharmacy, Ss Cyril and Methodius University in Skopje, 1000 Skopje, North Macedonia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5086-9017","authenticated-orcid":false,"given":"Vladimir","family":"Dobri\u010di\u0107","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, 11221 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milena R.","family":"Simi\u0107","sequence":"additional","affiliation":[{"name":"Department of Organic Chemistry, Faculty of Pharmacy, University of Belgrade, 11221 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-9557-1454","authenticated-orcid":false,"given":"Maja","family":"Jurhar Pavlova","sequence":"additional","affiliation":[{"name":"Institute for Microbiology and Parasitology, Faculty of Medicine, Ss Cyril and Methodius University in Skopje, 1000 Skopje, North Macedonia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8494-3644","authenticated-orcid":false,"given":"Evgenija","family":"Mihajloska","sequence":"additional","affiliation":[{"name":"Institute for Pharmaceutical Chemistry, Faculty of Pharmacy, Ss Cyril and Methodius University in Skopje, 1000 Skopje, North Macedonia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zoran","family":"Sterjev","sequence":"additional","affiliation":[{"name":"Institute for Pharmaceutical Chemistry, Faculty of Pharmacy, Ss Cyril and Methodius University in Skopje, 1000 Skopje, North Macedonia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9012-2447","authenticated-orcid":false,"given":"Ana","family":"Poceva Panovska","sequence":"additional","affiliation":[{"name":"Institute for Applied Chemistry and Pharmaceutical Analysis, Faculty of Pharmacy, Ss Cyril and Methodius University in Skopje, 1000 Skopje, North Macedonia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3800","DOI":"10.1021\/acschemneuro.4c00339","article-title":"Alzheimer\u2019s Disease: Exploring the Landscape of Cognitive Decline","volume":"15","author":"Tenchov","year":"2024","journal-title":"ACS Chem. 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