{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T12:41:39Z","timestamp":1792500099083,"version":"4.5.0"},"reference-count":40,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2025,9,15]],"date-time":"2025-09-15T00:00:00Z","timestamp":1757894400000},"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>Nitric esters are among the compounds that can liberate nitrogen monoxide (NO) in the organism. Due to the vasodilatation caused by nitrogen monoxide, NO-donors have been shown to protect endothelial function, acting as vasodilators, promoting efficient oxygen supply to tissues, to lower blood pressure, and to inhibit platelet aggregation. Incorporation of a NO-liberating moiety in the structure of non-steroidal anti-inflammatory drugs results in anti-inflammatory agents that are safer for the gastrointestinal system. In this research, ibuprofen and naproxen, two commonly applied non-steroidal anti-inflammatory drugs (NSAID), non-selective inhibitors of cyclooxygenases, were used to design novel anti-inflammatory agents able to release NO in the organism. Thus, the NSAIDs were amidated with beta-alanine and L-proline, which were able to incorporate the 2-nitro-oxyethyl moiety as the NO donor. The resulting compounds were anti-inflammatory agents, found to be more potent than the mother drugs, demonstrating remarkable inhibition of cyclooxygenase-2 over cyclooxygenase-1 and the ability to release NO in vitro. Furthermore, two of the most active anti-inflammatory compounds proved to be effective hypolipidemic agents, decreasing plasma total cholesterol, triglycerides, and LDL-cholesterol in hyperlipidemic rats significantly. The most effective compound in all the above tests was the ibuprofen derivative 5, which inhibited COX-2 by 95%, decreased inflammation by 73%, and reduced all lipidemic indices by more than 50%. Furthermore, docking experiments of compound 5 on the active sites of COX-1 and COX-2 showed that it interacts intensely with the binding site of COX-2, and the binding energy is equivalent to that of the relevant to celecoxib selective COX-2 inhibitor 4-[5-(4-bromophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] benzenesulfonamide (SC-5580). In conclusion, the performed structural modifications resulted not only in the improvement of the anti-inflammatory activity, compared with the parent NSAID, but also acquired strong hypolipidemic activity. Thus, the combination of structural characteristics resulting in a decrease in lipidemia, with possible inhibition of atherosclerosis, due to their anti-inflammatory activity and vasodilatation ability, via the liberated NO, may constitute a useful rationale for new compounds.<\/jats:p>","DOI":"10.3390\/molecules30183744","type":"journal-article","created":{"date-parts":[[2025,9,15]],"date-time":"2025-09-15T16:27:33Z","timestamp":1757953653000},"page":"3744","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Nitrogen Monoxide Releasing Nitric Ester Derivatives of Ibuprofen and Naproxen as COX Inhibitors, Anti-Inflammatory and Hypolipidemic Compounds"],"prefix":"10.3390","volume":"30","author":[{"given":"Paraskevi","family":"Tziona","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotelian University of Thessaloniki, 54124 Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Panagiotis","family":"Theodosis-Nobelos","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, School of Health Sciences, Frederick University, Nicosia 1036, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dimitris","family":"Lepesiotis","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotelian University of Thessaloniki, 54124 Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonis","family":"Gavalas","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotelian University of Thessaloniki, 54124 Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleni A.","family":"Rekka","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotelian University of Thessaloniki, 54124 Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1609","DOI":"10.2174\/138161212799958512","article-title":"Mechanisms of Neutrophil-mediated Disease: Innovative Therapeutic Interventions","volume":"18","author":"Magrone","year":"2012","journal-title":"Curr. 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