{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T04:10:39Z","timestamp":1791951039783,"version":"4.3.4"},"reference-count":90,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T00:00:00Z","timestamp":1764288000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Chronic inflammation is implicated in the development of various multifactorial diseases, including cancer, diabetes, arthritis, cardiovascular disorders, Alzheimer\u2019s disease, and autoimmune diseases. The enzymes that play a key role in the onset of the inflammation are cyclooxygenases (COXs) and lipoxygenases (LOXs). In recent years, cinnamic acid hybrid molecules, particularly those incorporating a nitric oxide (NO) donor moiety, have attracted considerable attention as potential pharmacological agents for the treatment of multifactorial diseases. In the present study, novel cinnamic acid\u2013nitric oxide (NO) donor hybrids were synthesized as multitarget agents and evaluated for their antioxidant, anti-inflammatory, and cytotoxic properties. In particular, hybrids 5a\u2013i, 6a\u2013i, 9a\u2013i, and 11 were synthesized and evaluated as lipid peroxidation and LOX inhibitors, while selected molecules were further tested as COX-1 and COX-2 inhibitors. Hybrids 6a\u2013i, 9a\u2013i, and 11 that contain a NO donor moiety, were additionally tested as albumin denaturation inhibitors and for their ability to release NO. The results indicated that compound 9a is a promising multitarget agent, exhibiting the lowest IC50 for LOX inhibition, significant antioxidant activity, and the highest NO donor potency. Furthermore, compound 9e demonstrated significant inhibitory activity against both COX-2 and LOX, suggesting its potential as a dual COX\u2013LOX inhibitor. Additionally, compound 6i exhibited the strongest cytotoxic activity among the tested compounds, with EC50 values ranging from 36 to 45 \u03bcM across multiple cancer cell lines. All synthesized compounds were also evaluated through in silico studies.<\/jats:p>","DOI":"10.3390\/molecules30234582","type":"journal-article","created":{"date-parts":[[2025,12,3]],"date-time":"2025-12-03T16:47:37Z","timestamp":1764780457000},"page":"4582","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Design, Synthesis, Biological Evaluation, and In Silico Studies of Novel Multitarget Cinnamic Acid Hybrids"],"prefix":"10.3390","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5531-059X","authenticated-orcid":false,"given":"Ioanna-Chrysoula","family":"Tsopka","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Chemistry, School of Pharmacy, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0099-5653","authenticated-orcid":false,"given":"Eleni","family":"Pontiki","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, School of Pharmacy, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8604-9870","authenticated-orcid":false,"given":"Ioanna","family":"Sigala","sequence":"additional","affiliation":[{"name":"Laboratory of Biochemistry, Department of Chemistry, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3388-3850","authenticated-orcid":false,"given":"Eleni","family":"Nikolakaki","sequence":"additional","affiliation":[{"name":"Laboratory of Biochemistry, Department of Chemistry, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0016-932X","authenticated-orcid":false,"given":"Kyriakos C.","family":"Prousis","sequence":"additional","affiliation":[{"name":"Institute of Chemical Biology, National Hellenic Research Foundation, 48 Vassileos Constantinou Avenue, 11635 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1844-350X","authenticated-orcid":false,"given":"Dimitra","family":"Hadjipavlou-Litina","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, School of Pharmacy, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Fleit, H.B. 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