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It is a process that is increasing significantly with the aging population worldwide, has yet to be cured, and therefore challenges healthcare systems. The ability of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors to modulate neurotransmitter levels has made AChE\/BChE inhibitors central therapeutic targets in drug development studies for the treatment of AD. Previous studies have demonstrated the beneficial effects of pyrimidine derivatives on cognitive functions and highlighted their high therapeutic potential against neurodegenerative diseases. Considering the pharmacological importance of AChE\/BChE inhibitors and pyrimidine derivatives, this study investigated the inhibitory potential of seven different pyrimidine derivatives (\n                    <jats:bold>1\u20137<\/jats:bold>\n                    ) on AChE and BChE using both in vitro and in silico approaches. Analysis of IC\n                    <jats:sub>50<\/jats:sub>\n                    values indicated that compounds\n                    <jats:bold>1\u20137<\/jats:bold>\n                    (IC\n                    <jats:sub>50<\/jats:sub>\n                    : 14.89\u201377.70\u00a0nM) exhibited strong inhibitory effect. Compound\n                    <jats:bold>6<\/jats:bold>\n                    (IC\n                    <jats:sub>50<\/jats:sub>\n                    :14.89\u00a0nM) had the strongest inhibitory effect on AChE, while it showed a much weaker inhibitory effect against BChE (IC\n                    <jats:sub>50<\/jats:sub>\n                    : 357\u00a0nM), corresponding to an approximately 24-fold selectivity for AChE. Molecular modeling results indicate that compounds\n                    <jats:bold>6<\/jats:bold>\n                    and\n                    <jats:bold>7<\/jats:bold>\n                    exhibit favorable interactions within the active site of the enzyme. In addition, compounds\n                    <jats:bold>1<\/jats:bold>\n                    and\n                    <jats:bold>3<\/jats:bold>\n                    , which exhibited the strongest inhibitory effects on BChE, appear to display a multiple binding profile with the active site of BChE. Correlation and regression analyses indicated that compounds\n                    <jats:bold>1\u20137<\/jats:bold>\n                    display a structure\u2013activity relationship (SAR) consistent with strong inhibitory potency toward AChE, while showing comparatively weaker inhibition toward BChE.\n                  <\/jats:p>","DOI":"10.1007\/s00210-026-05347-0","type":"journal-article","created":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T08:35:48Z","timestamp":1776933348000},"page":"15227-15239","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Evaluation of pyrimidine-based compounds as AChE and BChE inhibitors: in vitro inhibition, molecular modeling, and statistical evaluation"],"prefix":"10.1007","volume":"399","author":[{"given":"Zuhal","family":"Al\u0131m","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeliz","family":"Demir","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,23]]},"reference":[{"key":"5347_CR1","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1016\/j.bioorg.2016.10.002","volume":"69","author":"S Ahmad","year":"2016","unstructured":"Ahmad S, Iftikhar F, Ullah F, Sadiq A, Rashid U (2016) Rational design and synthesis of dihydropyrimidine based dual binding site acetylcholinesterase inhibitors. 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