{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T23:14:20Z","timestamp":1789946060479,"version":"4.0.1"},"reference-count":24,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2016,11,23]],"date-time":"2016-11-23T00:00:00Z","timestamp":1479859200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the National Natural Science Foundation of Zhejiang Province of China","award":["Y12H300003"],"award-info":[{"award-number":["Y12H300003"]}]},{"name":"the high level innovation team and outstanding scholar project of Guangxi institutions of higher education","award":["gui jiao ren [2014] 49 hao"],"award-info":[{"award-number":["gui jiao ren [2014] 49 hao"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>In this study, a new series of 16 methyl salicylate derivatives bearing a piperazine moiety were synthesized and characterized. The in vivo anti-inflammatory activities of target compounds were investigated against xylol-induced ear edema and carrageenan-induced paw edema in mice. The results showed that all synthesized compounds exhibited potent anti-inflammatory activities. Especially, the anti-inflammatory activities of compounds M15 and M16 were higher than that of aspirin and even equal to that of indomethacin at the same dose. In addition, the in vitro cytotoxicity activities and anti-inflammatory activities of four target compounds were performed in RAW264.7 macrophages, and compound M16 was found to significantly inhibit the release of lipopolysaccharide (LPS)-induced interleukin (IL)-6 and tumor necrosis factor (TNF)-\u03b1 in a dose-dependent manner. In addition, compound M16 was found to attenuate LPS induced cyclooxygenase (COX)-2 up-regulation. The current preliminary study may provide information for the development of new and safe anti-inflammatory agents.<\/jats:p>","DOI":"10.3390\/molecules21111544","type":"journal-article","created":{"date-parts":[[2016,11,23]],"date-time":"2016-11-23T11:12:14Z","timestamp":1479899534000},"page":"1544","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Synthesis, Characterization, and Anti-Inflammatory Activities of Methyl Salicylate Derivatives Bearing Piperazine Moiety"],"prefix":"10.3390","volume":"21","author":[{"given":"Jingfen","family":"Li","sequence":"first","affiliation":[{"name":"Department of Life Science, Huzhou Teachers\u2019 College, Huzhou 313000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Yin","sequence":"additional","affiliation":[{"name":"School of Chemistry and Chemical Engineering, Guangxi University, Nanning 530004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisheng","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Chemistry and Chemical Engineering, Guangxi University, Nanning 530004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pengyun","family":"Liang","sequence":"additional","affiliation":[{"name":"School of Chemistry and Chemical Engineering, Guangxi University, Nanning 530004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Menghua","family":"Li","sequence":"additional","affiliation":[{"name":"School of Chemistry and Chemical Engineering, Guangxi University, Nanning 530004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xu","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Chemistry and Chemical Engineering, Guangxi University, Nanning 530004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lichuan","family":"Wu","sequence":"additional","affiliation":[{"name":"School of Chemistry and Chemical Engineering, Guangxi University, Nanning 530004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua","family":"Yang","sequence":"additional","affiliation":[{"name":"School of Chemistry and Chemical Engineering, Guangxi University, Nanning 530004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2016,11,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1111\/j.1365-2249.2006.03261.x","article-title":"Chronic inflammation: Importance of NOD2 and NALP3 in interleukin-1\u03b2 generation","volume":"147","author":"Nielsen","year":"2007","journal-title":"Clin. Exp. Immunol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"772","DOI":"10.1038\/nri1937","article-title":"Adipocytokines: Mediators linking adipose tissue, inflammation and immunity","volume":"6","author":"Tilg","year":"2006","journal-title":"Nat. Rev. Immunol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1038\/nrd3226","article-title":"Pain market","volume":"9","author":"Melnikova","year":"2010","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1954","DOI":"10.1021\/jm701450q","article-title":"Second-generation aspirin and indomethacin prodrugs possessing an O2-(acetoxymethyl)-1-(2-carboxypyrrolidin-1-yl)diazenium-1,2-diolate nitric oxide donor moiety: Design, synthesis, biological evaluation, and nitric oxide release studies","volume":"51","author":"Velazquez","year":"2008","journal-title":"J. Med. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1016\/S0223-5234(00)00150-1","article-title":"The pyrrole moiety as a template for COX-1\/COX-2 inhibitors","volume":"35","author":"Dannhardt","year":"2000","journal-title":"Eur. J. Med. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/S0248-8663(99)83037-9","article-title":"Treatment of rheumatoid polyarthritis: Evolution of concepts and strategies","volume":"20","author":"Dubost","year":"1999","journal-title":"Rev. Med. Interne"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1211\/jpp\/61.03.0008","article-title":"Preclinical pharmacokinetic and pharmacodynamic evaluation of thiazolidinone PG15: An anti-inflammatory candidate","volume":"61","author":"Galdino","year":"2009","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"4138","DOI":"10.1016\/j.bmcl.2011.05.105","article-title":"Synthesis and anti-inflammatory activity of some novel 3-phenyl-N-[3-(4-phenylpiperazin-1yl)propyl]-1H-pyrazole-5-carboxamide derivatives","volume":"21","author":"Nagarapu","year":"2011","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_9","first-page":"1141","article-title":"Antitussive properties of levodropropizine","volume":"38","author":"Malandrino","year":"1988","journal-title":"Arzneim. Forsch."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"5785","DOI":"10.3390\/molecules16075785","article-title":"Design, synthesis and biological activity evaluation of arylpiperazine derivatives for the treatment of neuropathic pain","volume":"16","author":"Chen","year":"2011","journal-title":"Molecules"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.ejphar.2008.06.095","article-title":"Cloning and pharmacological characterization of the dog histamine H4 receptor","volume":"592","author":"Jiang","year":"2008","journal-title":"Eur. J. Pharmacol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1124\/jpet.103.061754","article-title":"A potent and selective histamine H4 receptor antagonist with anti-inflammatory properties","volume":"309","author":"Thurmond","year":"2004","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"56","DOI":"10.2174\/1389557513666131211110004","article-title":"Naturally occurring methyl salicylate glycosides","volume":"14","author":"Mao","year":"2014","journal-title":"Mini Rev. Med. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3526","DOI":"10.1111\/bph.12715","article-title":"Methyl salicylate lactoside inhibits inflammatory response of fibroblast-like synoviocytes and joint destruction in collagen-induced arthritis in mice","volume":"171","author":"Xin","year":"2014","journal-title":"Br. J. Pharmacol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/j.intimp.2015.01.024","article-title":"Anti-inflammation effect of methyl salicylate 2-O-\u03b2-d-lactoside on adjuvant induced-arthritis rats and lipopolysaccharide (LPS)-treated murine macrophages RAW264.7 cells","volume":"25","author":"Zhang","year":"2015","journal-title":"Int. Immunopharmacol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1016\/j.drugalcdep.2011.10.007","article-title":"Piperazine compounds as drugs of abuse","volume":"122","author":"Arbo","year":"2012","journal-title":"Drug Alcohol. Depend."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1097\/00007691-200404000-00007","article-title":"Chemistry, pharmacology, toxicology, and hepatic metabolism of designer drugs of the amphetamine (ecstasy), piperazine, and pyrrolidinophenone types: A synopsis","volume":"26","author":"Maurer","year":"2004","journal-title":"Ther. Drug Monit."},{"key":"ref_18","unstructured":"(1993). Drugs for parasitic infections. Med. Lett. Drugs Ther., 35, 111\u2013122."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1093\/jac\/33.4.685","article-title":"Structure-activity and structure-side-effect relationships for the quinolone antibacterials","volume":"33","author":"Domagala","year":"1994","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_20","first-page":"35","article-title":"Endotoxin as a therapeutic target in septic shock","volume":"2","author":"Corriveau","year":"1993","journal-title":"Infect. Agents Dis."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2195","DOI":"10.1101\/gad.1228704","article-title":"Signaling to NF-\u03baB","volume":"18","author":"Hayden","year":"2004","journal-title":"Genes. Dev."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1016\/S0039-6060(05)80327-7","article-title":"Mechanisms of reprogrammed macrophage endotoxin signal transduction after lipopolysaccharide pretreatment","volume":"118","author":"West","year":"1995","journal-title":"Surgery"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"6142","DOI":"10.1073\/pnas.0601805103","article-title":"Partnering between monomers of cyclooxygenase-2 homodimers","volume":"103","author":"Yuan","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"544","DOI":"10.3181\/00379727-111-27849","article-title":"Carrageenin-induced edema in hind paw of the rat as an assay for anti-iflammatory drugs","volume":"111","author":"Winter","year":"1962","journal-title":"Exp. Biol. Med."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/21\/11\/1544\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T19:27:19Z","timestamp":1760210839000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/21\/11\/1544"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,11,23]]},"references-count":24,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2016,11]]}},"alternative-id":["molecules21111544"],"URL":"https:\/\/doi.org\/10.3390\/molecules21111544","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,11,23]]}}}