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Following the 3Rs principle, this study assessed the in vitro pharmacokinetic properties of thiourea derivatives of naproxen (\n                    <jats:bold>1<\/jats:bold>\n                    \u2013\n                    <jats:bold>14<\/jats:bold>\n                    ). Permeability assessment using the parallel artificial membrane permeability assay method revealed that derivatives\n                    <jats:bold>4<\/jats:bold>\n                    (\u2010logPe = 4.13,\n                    <jats:italic>p<\/jats:italic>\n                    = 0.0859) and\n                    <jats:bold>7<\/jats:bold>\n                    (\u2010logPe = 3.94,\n                    <jats:italic>p<\/jats:italic>\n                    = 0.2291) exhibited the highest passive gastrointestinal absorption potential, comparable to naproxen. Evaluation of binding affinity to human serum albumin (HSA) using the high\u2010performance affinity chromatography method identified two groups of compounds: high\u2010binding aromatic amine derivatives (except derivative\n                    <jats:bold>5<\/jats:bold>\n                    ) and low\u2010binding aromatic amino acid ester derivatives. Microsomal stability assays indicated that compound\n                    <jats:bold>7<\/jats:bold>\n                    underwent the most extensive metabolic degradation (65.83% decrease). These findings suggest that further structural optimisation of compound\n                    <jats:bold>7<\/jats:bold>\n                    , such as esterification with higher or branched alcohols, should lead to the improvement of HSA binding and reduction of metabolic susceptibility. Conversely, compound\n                    <jats:bold>4<\/jats:bold>\n                    combines favorable biological activity with a pharmacokinetic profile closely resembling that of naproxen. Although limited by the exclusive use of in vitro models and the absence of in vivo validation, this study provides valuable insights for the rational design of naproxen\u2010based thiourea derivatives with enhanced anti\u2010inflammatory and anticancer potential.\n                  <\/jats:p>","DOI":"10.1002\/cbdv.202502219","type":"journal-article","created":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T11:10:44Z","timestamp":1767870644000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["In Vitro Pharmacokinetic Profiling of Thiourea Derivatives of Naproxen With Anti\u2010Inflammatory and Anticancer Activity"],"prefix":"10.1002","volume":"23","author":[{"given":"Nikola","family":"Nedeljkovi\u0107","sequence":"first","affiliation":[{"name":"Department of Pharmacy, Faculty of Medical Sciences University of Kragujevac  Kragujevac Serbia"}],"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 University of Belgrade\u2010Faculty of Pharmacy  Belgrade Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Vesovi\u0107","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Faculty of Medical Sciences University of Kragujevac  Kragujevac Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ratomir","family":"Jeli\u0107","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Faculty of Medical Sciences University of Kragujevac  Kragujevac Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bojan","family":"Markovi\u0107","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry University of Belgrade\u2010Faculty of Pharmacy  Belgrade Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zorica","family":"Vuji\u0107","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry University of Belgrade\u2010Faculty of Pharmacy  Belgrade Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milo\u0161","family":"Nikoli\u0107","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Faculty of Medical Sciences University of Kragujevac  Kragujevac Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,1,8]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40256\u2010016\u20100200\u20105"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40266\u2010019\u201000660\u20101"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcpt.13182"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11938\u2010014\u20100029\u20104"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2023.115434"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.5414\/CP203696"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1517\/17460441.2014.877881"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2021.116588"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.3390\/ani9100754"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/prp2.863"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.scitotenv.2024.173244"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejps.2015.06.023"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1155\/2013\/439039"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/jmr.3105"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpba.2017.10.022"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.apsb.2018.04.003"},{"key":"e_1_2_9_18_1","doi-asserted-by":"crossref","unstructured":"R. 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