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Among the tested compounds, rosmanol demonstrated exceptional potency, with IC<jats:sub>50<\/jats:sub> values of 0.73\u2009nM for AChE and 0.75\u2009nM for BChE, significantly outperforming tacrine. Rosmanol also exhibited remarkable inhibition of CA I (IC<jats:sub>50<\/jats:sub>\u2009=\u20090.21\u2009nM), surpassing acetazolamide by over 450\u2010fold, and moderate inhibition of CAII. Molecular docking and molecular mechanics generalized born surface area (MM\u2010GBSA) studies revealed strong binding affinities for rosmanol, with docking scores of \u221211.757\u2009kcal\/mol (AChE) and \u221211.465\u2009kcal\/mol (BChE). The MM\u2010GBSA binding free energy calculations further confirmed stable interactions for CA I (\u221263.24\u2009kcal\/mol) and AChE (\u221260.09\u2009kcal\/mol). Molecular dynamics simulations over 50\u2009ns showed stable enzyme\u2010ligand complexes, particularly for AChE and BChE (root mean square deviation ~1.5\u2009\u00c5), with key residues identified as crucial for stabilization. Other derivatives also displayed significant inhibitory activities, suggesting their potential as secondary leads. The ADMET analysis showed favorable pharmacokinetics and rosmanol emerged as a promising candidate. This comprehensive study highlights rosmanol as a multitarget therapeutic agent with potent anticholinesterase and CA inhibitory properties, offering promise for treating neurodegenerative and metabolic disorders.<\/jats:p>","DOI":"10.1002\/ardp.202400909","type":"journal-article","created":{"date-parts":[[2025,3,12]],"date-time":"2025-03-12T11:37:12Z","timestamp":1741779432000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Anticholinesterase and carbonic anhydrase inhibitory activities of natural carnosic acid derivatives: A comprehensive in vitro and in silico study"],"prefix":"10.1002","volume":"358","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0869-8517","authenticated-orcid":false,"given":"Zeynep","family":"K\u00f6ksal","sequence":"first","affiliation":[{"name":"Department of Chemistry, Faculty of Engineering and Natural Sciences Istanbul Medeniyet University  Istanbul T\u00fcrkiye"},{"name":"Science and Advanced Technologies Research Center (BILTAM) Istanbul Medeniyet University  Istanbul T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8333-035X","authenticated-orcid":false,"given":"Halil","family":"\u015eenol","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy Bezmialem Vakif University  Istanbul T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,3,12]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.foodchem.2015.01.090"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.3109\/14756366.2014.949254"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1016091631721"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1080\/14786419.2012.734820"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0031-9422(96)00709-1"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1080\/13880200701735411"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1080\/10942911003773916"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/slct.202300130"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1080\/10942912.2015.1020437"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00044-015-1424-7"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0706728"},{"key":"e_1_2_8_13_1","first-page":"619","volume":"37","author":"Topcu G.","year":"2013","journal-title":"Turk. 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