{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,24]],"date-time":"2025-12-24T05:20:37Z","timestamp":1766553637603,"version":"3.48.0"},"reference-count":62,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,12,22]],"date-time":"2025-12-22T00:00:00Z","timestamp":1766361600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001871","name":"FCT\u2014Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["UID\/PRR\/50026\/2025"],"award-info":[{"award-number":["UID\/PRR\/50026\/2025"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"FCT\u2014Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["UIDB\/04423\/2020"],"award-info":[{"award-number":["UIDB\/04423\/2020"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"FCT\u2014Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["LA\/P\/0101\/2020"],"award-info":[{"award-number":["LA\/P\/0101\/2020"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"FCT\u2014Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["PD\/BD\/135246\/2017"],"award-info":[{"award-number":["PD\/BD\/135246\/2017"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"FCT\u2014Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["COVID\/BD\/152012\/2021"],"award-info":[{"award-number":["COVID\/BD\/152012\/2021"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"FCT\u2014Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["2023.06754.CEECIND\/CP2841\/CT0014"],"award-info":[{"award-number":["2023.06754.CEECIND\/CP2841\/CT0014"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"FCT\u2014Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["PD\/00169\/2013"],"award-info":[{"award-number":["PD\/00169\/2013"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008814","name":"University of Minho","doi-asserted-by":"crossref","award":["UID\/50026"],"award-info":[{"award-number":["UID\/50026"]}],"id":[{"id":"10.13039\/501100008814","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001871","name":"FCT","doi-asserted-by":"publisher","award":["NORTE-01-0145-FEDER-000039"],"award-info":[{"award-number":["NORTE-01-0145-FEDER-000039"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"name":"FCT","award":["PINFRA\/22190\/2016 (Norte-01-0145-FEDER-022190)"],"award-info":[{"award-number":["PINFRA\/22190\/2016 (Norte-01-0145-FEDER-022190)"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Carboxyxanthones containing carboxylic acid groups linked to lipophilic aromatic rings resemble the key pharmacophoric features of many nonsteroidal anti-inflammatory drugs (NSAIDs). This structural similarity makes them attractive scaffolds for the development of new anti-inflammatory agents. This study describes the production, cytocompatibility, and anti-inflammatory potential of ten carboxyxanthones (1\u201310) and two intermediates (11\u201312) by evaluating their effects on key pro-inflammatory mediators, namely interleukin 6 (IL-6) and prostaglandin E2 (PGE2). As these compounds are produced by distinct mechanisms, their multi-target potential will be evaluated. Carboxyxanthones were obtained by multi-step pathways using different synthetic approaches through classical benzophenone or diaryl ether intermediates synthesis followed by intramolecular acylation. To the best of our knowledge, the synthesis of carboxyxanthones 3 and 5 is described herein for the first time. All tested compounds were cytocompatible with lipopolysaccharide (LPS)-stimulated macrophages. The most notable carboxyxanthones were 3, 4, 7, and 8, which were able to significantly reduce IL-6 production by approximately 60%. Molecular docking simulations between compounds 1\u201312 and cyclooxygenase-2 were conducted to characterize the structural features underlying molecular recognition, and to identify the most promising candidates for subsequent PGE2 assays. Carboxyxanthones 3, 5, and 6, as well as intermediate 12, were predicted to be the best. In the human in vitro inflammation model used, carboxyxanthone 6 exhibited the most potent and consistent inhibitory effect on PGE2 production. At the highest concentration tested (100 \u00b5M), it presented an efficacy comparable to that of celecoxib. Carboxyxanthones 3 and 5 demonstrated a biphasic effect, decreasing and increasing PGE2 production at lower (5, 12.5, and 25 \u00b5M) and higher (50 and 100 \u00b5M) concentrations, respectively. These results highlight the potential of carboxyxanthones as promising modulators of inflammatory pathways, paving the way for further studies aimed at elucidating their mechanisms of action, optimizing structural features, and assessing their safety and therapeutic potential in relevant disease models.<\/jats:p>","DOI":"10.3390\/ijms27010110","type":"journal-article","created":{"date-parts":[[2025,12,22]],"date-time":"2025-12-22T11:43:31Z","timestamp":1766403811000},"page":"110","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Evaluation of Cytocompatibility and Anti-Inflammatory Activity of Carboxyxanthones Selected by In Silico Studies"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-1193-002X","authenticated-orcid":false,"given":"Ricardo F.","family":"Pereira","sequence":"first","affiliation":[{"name":"Laborat\u00f3rio de Qu\u00edmica Org\u00e2nica e Farmac\u00eautica, Departamento de Ci\u00eancias Qu\u00edmicas, Faculdade de Farm\u00e1cia, Universidade do Porto, Rua Jorge Viterbo Ferreira n\u00b0 228, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7556-4826","authenticated-orcid":false,"given":"Catarina","family":"Amoedo-Leite","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Qu\u00edmica Org\u00e2nica e Farmac\u00eautica, Departamento de Ci\u00eancias Qu\u00edmicas, Faculdade de Farm\u00e1cia, Universidade do Porto, Rua Jorge Viterbo Ferreira n\u00b0 228, 4050-313 Porto, Portugal"}]},{"given":"Sara","family":"Gimondi","sequence":"additional","affiliation":[{"name":"3B\u2019s Research Group, I3BS\u2014Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, Parque de Ci\u00eancia e Tecnologia, Rua Ave 1, Edif\u00edcio 1 (Sede), Barco, 4805-694 Guimar\u00e3es, Portugal"},{"name":"ICVS\/3B\u2019s, PT Government Associate Laboratory, 4806-909 Braga\/Guimar\u00e3es, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9158-3114","authenticated-orcid":false,"given":"Sara F.","family":"Vieira","sequence":"additional","affiliation":[{"name":"3B\u2019s Research Group, I3BS\u2014Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, Parque de Ci\u00eancia e Tecnologia, Rua Ave 1, Edif\u00edcio 1 (Sede), Barco, 4805-694 Guimar\u00e3es, Portugal"},{"name":"ICVS\/3B\u2019s, PT Government Associate Laboratory, 4806-909 Braga\/Guimar\u00e3es, Portugal"}]},{"given":"Jo\u00e3o","family":"Handel","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Qu\u00edmica Org\u00e2nica e Farmac\u00eautica, Departamento de Ci\u00eancias Qu\u00edmicas, Faculdade de Farm\u00e1cia, Universidade do Porto, Rua Jorge Viterbo Ferreira n\u00b0 228, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1391-2143","authenticated-orcid":false,"given":"Andreia","family":"Palmeira","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Qu\u00edmica Org\u00e2nica e Farmac\u00eautica, Departamento de Ci\u00eancias Qu\u00edmicas, Faculdade de Farm\u00e1cia, Universidade do Porto, Rua Jorge Viterbo Ferreira n\u00b0 228, 4050-313 Porto, Portugal"},{"name":"CIIMAR\/CIMAR LA, Interdisciplinary Centre of Marine and Environmental Research, Universidade do Porto, Terminal de Cruzeiros do Porto de Leix\u00f5es, Avenida General Norton de Matos, s\/n, 4450-208 Matosinhos, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3320-730X","authenticated-orcid":false,"given":"Maria Elizabeth","family":"Tiritan","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Qu\u00edmica Org\u00e2nica e Farmac\u00eautica, Departamento de Ci\u00eancias Qu\u00edmicas, Faculdade de Farm\u00e1cia, Universidade do Porto, Rua Jorge Viterbo Ferreira n\u00b0 228, 4050-313 Porto, Portugal"},{"name":"CIIMAR\/CIMAR LA, Interdisciplinary Centre of Marine and Environmental Research, Universidade do Porto, Terminal de Cruzeiros do Porto de Leix\u00f5es, Avenida General Norton de Matos, s\/n, 4450-208 Matosinhos, Portugal"},{"name":"UCIBIO, Applied Molecular Biosciences Unit, Translational Toxicology Research Laboratory, University Institute of Health Sciences (1H-TOXRUN, IUCS-CESPU), 4585-116 Gandra, Portugal"},{"name":"Associate Laboratory i4HB\u2014Institute for Health and Bioeconomy, University Institute of Health Sciences\u2014CESPU, 4585-116 Gandra, Portugal"}]},{"given":"Madalena M. M.","family":"Pinto","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Qu\u00edmica Org\u00e2nica e Farmac\u00eautica, Departamento de Ci\u00eancias Qu\u00edmicas, Faculdade de Farm\u00e1cia, Universidade do Porto, Rua Jorge Viterbo Ferreira n\u00b0 228, 4050-313 Porto, Portugal"},{"name":"CIIMAR\/CIMAR LA, Interdisciplinary Centre of Marine and Environmental Research, Universidade do Porto, Terminal de Cruzeiros do Porto de Leix\u00f5es, Avenida General Norton de Matos, s\/n, 4450-208 Matosinhos, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3041-0687","authenticated-orcid":false,"given":"Nuno M.","family":"Neves","sequence":"additional","affiliation":[{"name":"3B\u2019s Research Group, I3BS\u2014Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, Parque de Ci\u00eancia e Tecnologia, Rua Ave 1, Edif\u00edcio 1 (Sede), Barco, 4805-694 Guimar\u00e3es, Portugal"},{"name":"ICVS\/3B\u2019s, PT Government Associate Laboratory, 4806-909 Braga\/Guimar\u00e3es, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3770-9393","authenticated-orcid":false,"given":"Helena","family":"Ferreira","sequence":"additional","affiliation":[{"name":"3B\u2019s Research Group, I3BS\u2014Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, Parque de Ci\u00eancia e Tecnologia, Rua Ave 1, Edif\u00edcio 1 (Sede), Barco, 4805-694 Guimar\u00e3es, Portugal"},{"name":"ICVS\/3B\u2019s, PT Government Associate Laboratory, 4806-909 Braga\/Guimar\u00e3es, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0940-9163","authenticated-orcid":false,"given":"Carla","family":"Fernandes","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Qu\u00edmica Org\u00e2nica e Farmac\u00eautica, Departamento de Ci\u00eancias Qu\u00edmicas, Faculdade de Farm\u00e1cia, Universidade do Porto, Rua Jorge Viterbo Ferreira n\u00b0 228, 4050-313 Porto, Portugal"},{"name":"CIIMAR\/CIMAR LA, Interdisciplinary Centre of Marine and Environmental Research, Universidade do Porto, Terminal de Cruzeiros do Porto de Leix\u00f5es, Avenida General Norton de Matos, s\/n, 4450-208 Matosinhos, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Fioranelli, M., Roccia, M.G., Flavin, D., and Cota, L. 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