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To address these limitations, four novel phosphorylated paracetamol analogs (2a\u20132d) were synthesized via a UV\u2010radical methodology and evaluated through integrated in silico, in vitro, and in vivo for anti\u2010inflammatory dermal approaches. Molecular docking suggested plausible binding interactions with COX\u20101 and COX\u20102 for all analogs. In vitro cytotoxicity assays in THP\u20101 cells showed that 2a and 2b did not affect cell viability at 100\u2009\u03bcM over 24\u2009h. In a TPA\u2010induced acute ear edema model in CD1 male mice, 2a produced about 50% inhibition of edema at the lowest tested quantity (0.5\u2009mg\/ear), representing a fourfold potency advantage over indomethacin at the same amount, while 2b displayed significant anti\u2010inflammatory and vasoregulatory activity at higher quantities. Computational ADME profiling indicated that all analogs satisfy Lipinski\u2019s drug\u2010likeness criteria and exhibit low predicted hERG channel risk. These results support N\u2010phosphorylation of 4\u2010aminophenol as a viable strategy to improve the topical anti\u2010inflammatory efficacy of paracetamol analogs.<\/jats:p>","DOI":"10.1002\/cmdc.70469","type":"journal-article","created":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T05:51:43Z","timestamp":1789105903000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Phosphorylated Analogs of Paracetamol and Their Anti\u2010Inflammatory Potential"],"prefix":"10.1002","volume":"21","author":[{"given":"Osvaldo Le\u00f3n de la","family":"Cruz","sequence":"first","affiliation":[{"name":"Instituto Polit\u00e9cnico Nacional Unidad Profesional Interdisciplinaria de Biotecnolog\u00eda  Mexico City Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2189-7908","authenticated-orcid":false,"given":"Gabriel Alfonso","family":"Guti\u00e9rrez\u2010Rebolledo","sequence":"additional","affiliation":[{"name":"Laboratorio de Toxicolog\u00eda Productos Naturales, Departamento Farmacia, Escuela Nacional de Ciencias Biol\u00f3gicas Instituto Polit\u00e9cnico Nacional  Mexico City Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6483-2875","authenticated-orcid":false,"given":"Carlos Zepactonal G\u00f3mez","family":"Castro","sequence":"additional","affiliation":[{"name":"SECIHTI Universidad Aut\u00f3noma del Estado de Hidalgo  Mineral de La Reforma Hidalgo M\u00e9xico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-9628-4576","authenticated-orcid":false,"given":"\u00c1ngel Daniel Campos","family":"Ju\u00e1rez","sequence":"additional","affiliation":[{"name":"Instituto Polit\u00e9cnico Nacional Unidad Profesional Interdisciplinaria de Biotecnolog\u00eda  Mexico City Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5760-9955","authenticated-orcid":false,"given":"Porfirio Alonso","family":"Ruiz\u2010Hurtado","sequence":"additional","affiliation":[{"name":"Laboratorio de Toxicolog\u00eda Molecular, Departamento Farmacia, Escuela Nacional de Ciencias Biol\u00f3gicas Instituto Polit\u00e9cnico Nacional  Mexico City Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8186-4772","authenticated-orcid":false,"given":"Josu\u00e9","family":"Rodr\u00edguez\u2010Lozada","sequence":"additional","affiliation":[{"name":"Universidad Polit\u00e9cnica de Tlaxcala  Tepeyanco Tlaxcala M\u00e9xico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2808-2808","authenticated-orcid":false,"given":"Jos\u00e9 Luis","family":"Castrej\u00f3n\u2010Flores","sequence":"additional","affiliation":[{"name":"Instituto Polit\u00e9cnico Nacional Unidad Profesional Interdisciplinaria de Biotecnolog\u00eda  Mexico City Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7253-363X","authenticated-orcid":false,"given":"Mar\u00eda Guadalupe","family":"Ram\u00edrez\u2010Sotelo","sequence":"additional","affiliation":[{"name":"Instituto Polit\u00e9cnico Nacional Unidad Profesional Interdisciplinaria de Biotecnolog\u00eda  Mexico City Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1921-778X","authenticated-orcid":false,"given":"Marco","family":"Franco\u2010P\u00e9rez","sequence":"additional","affiliation":[{"name":"Departamento de F\u00edsica y Qu\u00edmica Te\u00f3rica, Facultad de Qu\u00edmica Universidad Nacional Aut\u00f3noma de M\u00e9xico  Mexico City M\u00e9xico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4920-3768","authenticated-orcid":false,"given":"Angel","family":"Zamudio\u2010Medina","sequence":"additional","affiliation":[{"name":"Instituto Polit\u00e9cnico Nacional Unidad Profesional Interdisciplinaria de Biotecnolog\u00eda  Mexico City Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,10]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jchemed.3c00549"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10787\u2010998\u20100031"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.4314\/bcse.v35i1.6"},{"key":"e_1_2_9_5_1","first-page":"145","article-title":"Synthesis, Characterization and Antibacterial Properties of Some Heteroleptic Metal (II) Complexes of Paracetamol and Vanillin","volume":"7","author":"Osowole A. 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