{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T18:21:55Z","timestamp":1780338115778,"version":"3.54.1"},"reference-count":48,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2021,7,2]],"date-time":"2021-07-02T00:00:00Z","timestamp":1625184000000},"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>A series of L-serine amides of antioxidant acids, such as Trolox, (E)-3-(3,5-di-tert-butyl-4-hydroxyphenyl)acrylic acid (phenolic derivative of cinnamic acid) and 3,5-di-tert-butyl-4-hydroxybenzoic acid (structurally similar to butylated hydroxytoluene), was synthesized. The hydroxy group of serine was esterified with two classical NSAIDs, ibuprofen and ketoprofen. The Trolox derivatives with ibuprofen (7) and ketoprofen (10) were the most potent inhibitors of lipid peroxidation (IC50 3.4 \u03bc\u039c and 2.8 \u03bc\u039c), several times more potent than the reference Trolox (IC50 25 \u03bc\u039c). Most of the compounds decreased carrageenan-induced rat paw edema (37\u201367% at 150 \u03bcmol\/kg). They were moderate inhibitors of soybean lipoxygenase, with the exception of ibuprofen derivative 8 (IC50 13 \u03bc\u039c). The most active anti-inflammatory compounds exhibited a significant decrease in lipidemic indices in the plasma of Triton-induced hyperlipidemic rats, e.g., the most active compound 9 decreased triglycerides, total cholesterol and low-density lipoprotein cholesterol by 52%, 61% and 70%, respectively, at 150 \u03bcmol\/kg (i.p.), similar to that of simvastatin, a well-known hypocholesterolemic drug. Since the designed compounds seem to exhibit multiple pharmacological actions, they may be of use for the development of agents against inflammatory and degenerative conditions.<\/jats:p>","DOI":"10.3390\/molecules26134060","type":"journal-article","created":{"date-parts":[[2021,7,2]],"date-time":"2021-07-02T10:06:34Z","timestamp":1625220394000},"page":"4060","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Antioxidant Serine-(NSAID) Hybrids with Anti-Inflammatory and Hypolipidemic Potency"],"prefix":"10.3390","volume":"26","author":[{"given":"Panagiotis","family":"Theodosis-Nobelos","sequence":"first","affiliation":[{"name":"Department of Pharmacy, School of Health Sciences, Frederick University, Nicosia 1036, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georgios","family":"Papagiouvannis","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, School of Health Sciences, Frederick University, Nicosia 1036, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paraskevi","family":"Tziona","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotelian University of Thessaloniki, 54124 Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Panos N.","family":"Kourounakis","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, School of Health Sciences, Frederick University, Nicosia 1036, Cyprus"},{"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":[[2021,7,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.cmet.2010.12.008","article-title":"Nf-\u03bab, inflammation and metabolic disease","volume":"13","author":"Baker","year":"2011","journal-title":"Cell Metab."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1161\/CIRCRESAHA.117.311401","article-title":"Reactive Oxygen Species in Metabolic and Inflammatory Signaling","volume":"122","author":"Forrester","year":"2018","journal-title":"Circ. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1111\/imm.12922","article-title":"Inflammation in CNS neurodegenerative diseases","volume":"154","author":"Stephenson","year":"2018","journal-title":"Immunology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1134","DOI":"10.2174\/1381612820666141014142557","article-title":"Reactive oxygen species in pathogenesis of atherosclerosis","volume":"21","author":"Nikolay","year":"2015","journal-title":"Curr. Pharm. Des."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1128\/MCB.26.1.140-154.2006","article-title":"Nox2 and rac1 regulate H2O2-dependent recruitment of traf6 to endosomal interleukin-1 receptor complexes","volume":"26","author":"Li","year":"2006","journal-title":"Mol. Cell. Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"3589","DOI":"10.4049\/jimmunol.173.6.3589","article-title":"Cutting edge: Direct interaction of tlr4 with nad(p)h oxidase 4 isozyme is essential for lipopolysaccharide-induced production of reactive oxygen species and activation of nf-\u03bab","volume":"173","author":"Park","year":"2004","journal-title":"J. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1161\/CIRCRESAHA.112.266593","article-title":"Gene silencing of the mitochondrial adaptor p66shc suppresses vascular hyperglycemic memory in diabetes","volume":"111","author":"Paneni","year":"2012","journal-title":"Circ. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.lfs.2016.04.019","article-title":"Aqueous or lipid components of atherosclerotic lesion increase macrophage oxidation and lipid accumulation","volume":"154","author":"Aviram","year":"2016","journal-title":"Life Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3863726","DOI":"10.1155\/2016\/3863726","article-title":"Modulation of Hypercholesterolemia-Induced Oxidative\/Nitrative Stress in the Heart","volume":"2016","author":"Csonka","year":"2016","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1259","DOI":"10.1016\/j.bmc.2011.12.030","article-title":"Design, synthesis, biological evaluation, and comparative Cox1 and Cox2 docking of p-substituted benzylidenamino phenyl esters of ibuprofenic and mefenamic acids","volume":"20","author":"Hegazy","year":"2012","journal-title":"Bioorg. Med. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/S0300-483X(99)00208-5","article-title":"Reduction of gastrointestinal toxicity of NSAIDs via molecular modifications leading to antioxidant anti-inflammatory drugs","volume":"144","author":"Kourounakis","year":"2000","journal-title":"Toxicology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1097\/FJC.0b013e318157f72d","article-title":"COX-2 inhibitors and cardiovascular risk","volume":"50","author":"Funk","year":"2007","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"408","DOI":"10.2174\/1573406413666170209123433","article-title":"Medicinal Chemistry approaches of controlling gastrointestinal side effects of non-steroidal anti-inflammatory drugs. Endogenous protective mechanisms and drug design","volume":"13","author":"Tziona","year":"2017","journal-title":"Med. Chem."},{"key":"ref_14","first-page":"209","article-title":"Antioxidant and cytoprotective effects of L-Serine on human endothelial cells","volume":"7","author":"Maralani","year":"2012","journal-title":"Res. Pharm. Sci."},{"key":"ref_15","first-page":"126","article-title":"Antioxidant effects of L-Serine against fatty streak formation in hypercholesterolemic animals","volume":"2","author":"Movahedian","year":"2010","journal-title":"ARYA Atheroscler."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"4735","DOI":"10.1172\/JCI57549","article-title":"Oral L-serine supplementation reduces production of neurotoxic deoxysphingolipids in mice and humans with hereditary sensory autonomic neuropathy type 1","volume":"121","author":"Garofalo","year":"2011","journal-title":"J. Clin. Investig."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"4926","DOI":"10.1073\/pnas.97.9.4926","article-title":"D-serine is an endogenous ligand for the glycine site of the N-methyl-D-aspartate receptor","volume":"25","author":"Mothet","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1002\/ana.410440219","article-title":"Beneficial effects of L-serine and glycine in the management of seizures in 3-phosphoglycerate dehydrogenase deficiency","volume":"44","author":"Duran","year":"1998","journal-title":"Ann. Neurol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1042\/bj20021785","article-title":"L-serine in disease and development","volume":"371","author":"Snell","year":"2003","journal-title":"Biochem. J."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.jep.2013.08.019","article-title":"Protective effects of cinnamic acid and cinnamic aldehyde on isoproterenol-induced acute myocardial ischemia in rats","volume":"150","author":"Song","year":"2013","journal-title":"J. Ethnopharmacol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"429320","DOI":"10.1155\/2012\/429320","article-title":"Anti-Inflammatory Activities of Cinnamomum cassia Constituents In Vitro and In Vivo","volume":"2012","author":"Liao","year":"2012","journal-title":"Evid. Based Complement. Altern. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"111148","DOI":"10.1016\/j.fct.2020.111148","article-title":"Anti-obesity effect of trans-cinnamic acid on HepG2 cells and HFD-fed mice","volume":"137","author":"Wang","year":"2020","journal-title":"Food Chem. Toxicol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"5616","DOI":"10.1016\/j.bmc.2006.04.030","article-title":"New analogues of butylated hydroxytoluene as anti-inflammatory and antioxidant agents","volume":"14","author":"Ziakas","year":"2006","journal-title":"Bioorg. Med. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"106893","DOI":"10.1016\/j.intimp.2020.106893","article-title":"Anti-inflammatory and antinociceptive activity profile of a new lead compound\u2014LQFM219","volume":"88","author":"Florentino","year":"2020","journal-title":"Int. Immunopharmacol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"10","DOI":"10.2174\/1389557520666200807132617","article-title":"A Review on Vitamin E Natural Analogues and on the Design of Synthetic Vitamin E Derivatives as Cytoprotective Agents","volume":"21","author":"Papagiouvannis","year":"2021","journal-title":"Mini Rev. Med. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"214","DOI":"10.2174\/1573406412666161104122310","article-title":"Anti-inflammatory and Hypolipidemic Effect of Novel Conjugates with Trolox and Other Antioxidant Acids","volume":"13","author":"Kourounakis","year":"2017","journal-title":"Med. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"7092151","DOI":"10.1155\/2019\/7092151","article-title":"Vascular Inflammation and Oxidative Stress: Major Triggers for Cardiovascular Disease","volume":"2019","author":"Steven","year":"2019","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1634","DOI":"10.1111\/j.1471-4159.2006.03907.x","article-title":"Oxidative stress and neurodegeneration: Where are we now?","volume":"97","author":"Halliwell","year":"2006","journal-title":"J. Neurochem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"4800","DOI":"10.1016\/j.bmcl.2017.09.054","article-title":"Dual antioxidant structures with potent anti-inflammatory, hypolipidemic and cytoprotective properties","volume":"27","author":"Athanasekou","year":"2017","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"292","DOI":"10.4103\/0253-7613.157127","article-title":"A study of the mechanisms underlying the anti-inflammatory effect of ellagic acid in carrageenan-induced paw edema in rats","volume":"47","author":"Mansouri","year":"2015","journal-title":"Indian J. Pharmacol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1007\/s00044-016-1767-8","article-title":"Novel polyfunctional esters of ibuprofen and ketoprofen with hypolipidemic, lipoxygenase inhibitory and enhanced anti-inflammatory activity","volume":"26","author":"Tziona","year":"2017","journal-title":"Med. Chem. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"910","DOI":"10.1016\/j.bmcl.2015.12.063","article-title":"Amides of non-steroidal anti-inflammatory drugs with thiomorpholine can yield hypolipidemic agents with improved anti-inflammatory activity","volume":"26","author":"Kourti","year":"2016","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2462","DOI":"10.2174\/1568026614666141203120425","article-title":"Selected heterocyclic compounds as antioxidants. Synthesis and biological evaluation","volume":"14","author":"Tsolaki","year":"2014","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1397","DOI":"10.1590\/0001-3765201520150056","article-title":"Antioxidant, analgesic and anti-inflammatory effects of lavender essential oil","volume":"87","author":"Silva","year":"2015","journal-title":"An. Acad. Bras. Cienc."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1016\/j.phymed.2013.09.001","article-title":"Antioxidant and intestinal anti-inflammatory effects of plant-derived coumarin derivatives","volume":"21","author":"Witaicenis","year":"2014","journal-title":"Phytomedicine"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1111\/bcpt.12114","article-title":"Recent advances in the search for novel 5-lipoxygenase inhibitors","volume":"114","author":"Steinhilber","year":"2014","journal-title":"Basic Clin. Pharmacol. Toxicol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1812","DOI":"10.1016\/j.bbapap.2008.07.004","article-title":"Development of novel peptide inhibitor of Lipoxygenase based on biochemical and BIAcore evidences","volume":"1784","author":"Somvanshi","year":"2008","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1016\/j.ejps.2018.06.003","article-title":"Safer anti-inflammatory therapy through dual COX-2\/5-LOX inhibitors: A structure-based approach","volume":"121","author":"Manju","year":"2018","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Theodosis-Nobelos, P., Papagiouvanis, G., Pantelidou, M., Kourounakis, P.N., Athanasekou, C., and Rekka, E.A. (2020). Design, synthesis and study of nitrogen monoxide donors as potent hypolipidaemic and anti-inflammatory agents. Molecules, 25.","DOI":"10.3390\/molecules25010019"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Theodosis-Nobelos, P., Papagiouvannis, G., Kourounakis, P.N., and Rekka, E.A. (2019). Active Anti-Inflammatory and Hypolipidemic Derivatives of Lorazepam. Molecules, 24.","DOI":"10.3390\/molecules24183277"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"e04304","DOI":"10.1016\/j.heliyon.2020.e04304","article-title":"Avenanthramides as lipoxygenase inhibitors","volume":"6","author":"Landberg","year":"2020","journal-title":"Heliyon"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"5028","DOI":"10.1016\/j.bmcl.2015.10.036","article-title":"Esters of some non-steroidal anti-inflammatory drugs with cinnamyl alcohol are potent lipoxygenase inhibitors with enhanced anti-inflammatory activity","volume":"25","author":"Kourti","year":"2015","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1007\/s10517-010-0994-0","article-title":"Fractional composition of blood serum lipoproteins in mice and rats with Triton WR 1339-induced lipemia","volume":"149","author":"Korolenko","year":"2010","journal-title":"Bull. Exp. Biol. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.2174\/0929867043365369","article-title":"Oxidative stress, antioxidants, and endothelial function","volume":"11","author":"Schulz","year":"2004","journal-title":"Curr. Med. Chem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"119","DOI":"10.3389\/fnagi.2015.00119","article-title":"Oxidized cholesterol as the driving force behind the development of Alzheimer\u2019s disease","volume":"7","author":"Gamba","year":"2015","journal-title":"Front. Aging Neurosci."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Lorenzon Dos Santos, J., Quadros, A.S., Weschenfelder, C., Garofallo, S.B., and Marcadenti, A. (2020). Oxidative Stress Biomarkers, Nut-Related Antioxidants, and Cardiovascular Disease. Nutrients, 12.","DOI":"10.3390\/nu12030682"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"127","DOI":"10.2174\/2212796811666170509123209","article-title":"Synthesis, antioxidant and anti-inflammatory effects of antioxidant acid amides with GABA and n-acyl-pyrrolidin-2-ones","volume":"11","author":"Tsiakitzis","year":"2017","journal-title":"Curr. Chem. Biol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1002\/ardp.201500147","article-title":"Thiomorpholine derivatives with hypolipidemic and antioxidant activity","volume":"348","author":"Tooulia","year":"2015","journal-title":"Arch. Pharm."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/26\/13\/4060\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:25:11Z","timestamp":1760163911000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/26\/13\/4060"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,2]]},"references-count":48,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2021,7]]}},"alternative-id":["molecules26134060"],"URL":"https:\/\/doi.org\/10.3390\/molecules26134060","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,2]]}}}