{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T11:10:28Z","timestamp":1785409828314,"version":"3.56.0"},"reference-count":85,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T00:00:00Z","timestamp":1783468800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University of Ha'il","award":["RG-23 108"],"award-info":[{"award-number":["RG-23 108"]}]},{"award":["RG-23 108"],"award-info":[{"award-number":["RG-23 108"]}],"id":[{"id":"https:\/\/ror.org\/013w98a82","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Thienopyrimidine derivatives are emerging as potent scaffolds for cholinesterase inhibition in Alzheimer\u2019s disease therapy. In this work, a novel series of substituted thieno[2,3-d]pyrimidines was synthesized via Gewald\u2019s reaction, followed by cyclization and functionalization through nucleophilic substitution and hydrazone formation. Structural confirmation was achieved using spectroscopic techniques, and biological evaluation was performed against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), with donepezil and rivastigmine as reference drugs. Compound 4 emerged as the most potent and selective AChE inhibitor (IC50 = 0.58 \u00b5M), while compound 7 also showed strong AChE inhibition (IC50 = 0.63 \u00b5M). Notably, compound 9 exhibited superior BChE inhibition (IC50 = 3.05 \u00b5M) compared to donepezil (IC50 = 8.41 \u00b5M). Dual inhibitory activity was observed for compounds 5, 6, and 11, highlighting their multitarget potential. Molecular dynamics simulations (200 ns) and MM\/GBSA binding free energy calculations provided mechanistic insights. Compound 4 showed the most favorable binding energy (\u0394Gbind = \u221259.16 kcal\/mol), driven by hydrogen bonds with Tyr121 and Glu199 and \u03c0-\u03c0 stacking with Trp83. Residue-level decomposition identified Tyr121, Trp83, Glu199, and Tyr338 as critical contributors to binding stability. Structure\u2013activity relationship analysis confirmed that nitrogen-containing substituents and cyclic amino moieties enhance potency, whereas bulky aromatic groups reduce activity. These findings establish thieno[2,3-d]pyrimidine derivatives as promising candidates for the development of next-generation anti-Alzheimer agents.<\/jats:p>","DOI":"10.3390\/ijms27146119","type":"journal-article","created":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T17:27:31Z","timestamp":1783531651000},"page":"6119","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Synthesis, Biological Evaluation, Molecular Docking and Molecular Dynamics of Substituted Thieno[2,3-d]pyrimidine Derivatives as Potential Anti-Alzheimer Agents"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8949-856X","authenticated-orcid":false,"given":"Asma K.","family":"Alshamari","sequence":"first","affiliation":[{"name":"Department of Chemistry, College of Science, Ha\u2019il University, Ha\u2019il 81451, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nourhan","family":"Magdy","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Faculty of Science, Menofia University, Shbien El-Kom 32511, Egypt"},{"name":"Department of Photochemistry, Synthetic Unit, Chemical Industries Research Institute, National Research Centre, 33 El Buhouth Street, Cairo P.O. Box 12622, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ebtesam A.","family":"Basiony","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Faculty of Science, Menofia University, Shbien El-Kom 32511, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1809-9232","authenticated-orcid":false,"given":"Nasser A.","family":"Hassan","sequence":"additional","affiliation":[{"name":"Department of Photochemistry, Synthetic Unit, Chemical Industries Research Institute, National Research Centre, 33 El Buhouth Street, Cairo P.O. Box 12622, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1176-7103","authenticated-orcid":false,"given":"Odeh A. O.","family":"Alshammari","sequence":"additional","affiliation":[{"name":"Department of Chemistry, College of Science, Ha\u2019il University, Ha\u2019il 81451, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adel A.-H.","family":"Abdel-Rahman","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Faculty of Science, Menofia University, Shbien El-Kom 32511, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-9161-746X","authenticated-orcid":false,"given":"Nuha O. S.","family":"Alsaif","sequence":"additional","affiliation":[{"name":"Department of Chemistry, College of Science, Ha\u2019il University, Ha\u2019il 81451, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mona Z.","family":"Alshammari","sequence":"additional","affiliation":[{"name":"Department of Chemistry, College of Science, Ha\u2019il University, Ha\u2019il 81451, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed A.","family":"Elrashedy","sequence":"additional","affiliation":[{"name":"Natural and Microbial Chemistry Department, Pharmaceutical and Drug Industries Research Institute, National Research Centre, 33 El Buhouth Street, Cairo P.O. Box 12622, Egypt"},{"name":"College of Pharmacy, Al-Farahidi University, Baghdad 10021, Iraq"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3123-1026","authenticated-orcid":false,"given":"Allam A.","family":"Hassan","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Faculty of Science, Suez University, Suez 43221, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1016\/j.tins.2014.08.004","article-title":"Lost after translation: Missorting of Tau protein and consequences for Alzheimer disease","volume":"37","author":"Zempel","year":"2014","journal-title":"Trends Neurosci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"311","DOI":"10.3233\/JAD-2010-1221","article-title":"Alzheimer\u2019s Disease and the Amyloid-\u03b2 Peptide","volume":"19","author":"Lovell","year":"2010","journal-title":"J. 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