{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,5]],"date-time":"2026-03-05T06:41:50Z","timestamp":1772692910560,"version":"3.50.1"},"reference-count":20,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T00:00:00Z","timestamp":1772496000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003593","name":"CNPq","doi-asserted-by":"crossref","award":["442831\/2023-4\/Projetos Int 2023"],"award-info":[{"award-number":["442831\/2023-4\/Projetos Int 2023"]}],"id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001807","name":"FAPESP","doi-asserted-by":"publisher","award":["17\/20291-0"],"award-info":[{"award-number":["17\/20291-0"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001807","name":"FAPESP","doi-asserted-by":"publisher","award":["25\/04557-7"],"award-info":[{"award-number":["25\/04557-7"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["DDC"],"abstract":"<jats:p>Background\/Objectives: The study investigated the anti-inflammatory potential of neolignan derivatives of dehydrodieugenol (CP1\u2013CP5), focusing on the inhibition of secretory phospholipase A2 (sPLA2), a key enzyme in inflammation. Methods: Comprehensive quantitative docking analysis using four independent algorithms (PLP, ASP, ChemScore, GoldScore) revealed exceptional multitarget binding profiles for CP1 and CP2, with scores consistently above activity thresholds for acetylcholinesterase (AChE), cyclooxygenase-2 (COX-2), and sPLA2 from Crotalus durissus terrificus in both monomeric (Mcdt) and quaternary (Tcdt) forms. Results: Among the compounds, CP1 demonstrated the highest predicted affinity (AChE: 78.5, COX-2: 83.8, sPLA2: 82.7\u201383.4) and most potent experimental activity, reducing sPLA2 catalytic velocity through mixed-type inhibition involving the active site (His47, Asp48) and Ca2+ binding loop. In vivo assays in sPLA2-induced paw edema demonstrated that CP1 and CP2 achieved remarkable anti-inflammatory effects (up to 68.3% reduction), significantly exceeding their protective potential by direct enzyme inhibition, confirming the multitarget mechanism. The strong correlation between predicted docking scores and paw edema reduction (R2 = 0.89, p &lt; 0.01) creates a firm foundation for establishing structure\u2013activity relationship explanations. Conclusions: These findings highlight an integrated mechanism involving: (1) partial sPLA2 modulation, (2) neuroimmune regulation via AChE inhibition, and (3) prostaglandin synthesis blockade through COX-2 inhibition. This multitarget approach, combined with the natural origin of the compounds, positions dehydrodieugenol derivatives as promising candidates for developing therapies against complex inflammatory diseases, offering significant advantages over single-target strategies.<\/jats:p>","DOI":"10.3390\/ddc5010020","type":"journal-article","created":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T12:48:56Z","timestamp":1772542136000},"page":"20","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Dehydrodieugenol Neolignans as Multitarget Anti-Inflammatory Agents: sPLA2 Inhibition and Therapeutic Implications"],"prefix":"10.3390","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-6594-9547","authenticated-orcid":false,"given":"Adeilso B.","family":"Santos Junior","sequence":"first","affiliation":[{"name":"BIOMOLPEP, Department of Biology, Institute of Biosciences UNESP\/CLP, S\u00e3o Vicente 11330-900, SP, Brazil"},{"name":"Postgraduate Studies in Biotechnoscience, Center for Natural and Human Sciences (CCNH), ABC Federal University (UFABC), Santo Andr\u00e9 09280-560, SP, Brazil"}]},{"given":"Caroline R. C.","family":"Costa","sequence":"additional","affiliation":[{"name":"BIOMOLPEP, Department of Biology, Institute of Biosciences UNESP\/CLP, S\u00e3o Vicente 11330-900, SP, Brazil"},{"name":"Institute of Sciences and Health, Paulista University (UNIP), Santos 11075-110, SP, Brazil"}]},{"given":"Jo\u00e3o H. G.","family":"Lago","sequence":"additional","affiliation":[{"name":"Postgraduate Studies in Biotechnoscience, Center for Natural and Human Sciences (CCNH), ABC Federal University (UFABC), Santo Andr\u00e9 09280-560, SP, Brazil"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4546-8013","authenticated-orcid":false,"given":"Airam","family":"Roggero","sequence":"additional","affiliation":[{"name":"BIOMOLPEP, Department of Biology, Institute of Biosciences UNESP\/CLP, S\u00e3o Vicente 11330-900, SP, Brazil"},{"name":"LAQV\/REQUIMTE-BioSIM, Department of Biomedicine, Faculty of Medicine, Porto University, 4200-319 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7883-115X","authenticated-orcid":false,"given":"Igor N.","family":"Oliveira","sequence":"additional","affiliation":[{"name":"BIOMOLPEP, Department of Biology, Institute of Biosciences UNESP\/CLP, S\u00e3o Vicente 11330-900, SP, Brazil"}]},{"given":"Danilo R. S.","family":"Lima","sequence":"additional","affiliation":[{"name":"BIOMOLPEP, Department of Biology, Institute of Biosciences UNESP\/CLP, S\u00e3o Vicente 11330-900, SP, Brazil"}]},{"given":"Paloma P.","family":"Borges","sequence":"additional","affiliation":[{"name":"BIOMOLPEP, Department of Biology, Institute of Biosciences UNESP\/CLP, S\u00e3o Vicente 11330-900, SP, Brazil"}]},{"given":"Willian H. B. C.","family":"Santos","sequence":"additional","affiliation":[{"name":"BIOMOLPEP, Department of Biology, Institute of Biosciences UNESP\/CLP, S\u00e3o Vicente 11330-900, SP, Brazil"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1192-7296","authenticated-orcid":false,"given":"Marcos A.","family":"Oliveira","sequence":"additional","affiliation":[{"name":"LABIMES, Department of Biology, Institute of Biosciences UNESP\/CLP, S\u00e3o Vicente 11330-900, SP, Brazil"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6560-5284","authenticated-orcid":false,"given":"S\u00e9rgio F.","family":"Sousa","sequence":"additional","affiliation":[{"name":"LAQV\/REQUIMTE-BioSIM, Department of Biomedicine, Faculty of Medicine, Porto University, 4200-319 Porto, Portugal"}]},{"given":"Marcos H.","family":"Toyama","sequence":"additional","affiliation":[{"name":"BIOMOLPEP, Department of Biology, Institute of Biosciences UNESP\/CLP, S\u00e3o Vicente 11330-900, SP, Brazil"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,3]]},"reference":[{"key":"ref_1","first-page":"6","article-title":"Polypharmacology: Challenges and opportunities in drug discovery","volume":"3","author":"Anighoro","year":"2014","journal-title":"Clin. Transl. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1021\/acs.jnatprod.9b01285","article-title":"Natural products as sources of new drugs over the nearly four decades from 01\/1981 to 09\/2019","volume":"83","author":"Newman","year":"2020","journal-title":"J. Nat. Prod."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"6130","DOI":"10.1021\/cr200085w","article-title":"Phospholipase A2 enzymes: Physical structure, biological function, disease implication, chemical inhibition, and therapeutic intervention","volume":"111","author":"Dennis","year":"2011","journal-title":"Chem. Rev."},{"key":"ref_4","first-page":"87","article-title":"Recent progress in phospholipase A2 research: From cells to animals to humans","volume":"132","author":"Murakami","year":"2011","journal-title":"Adv. Immunol."},{"key":"ref_5","first-page":"101875","article-title":"Phospholipase A2 structure\/function, mechanism, and signaling","volume":"297","author":"Burke","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_6","first-page":"159","article-title":"Biochemistry and physiology of mammalian secreted phospholipases A2","volume":"583","author":"Lambeau","year":"2008","journal-title":"Methods Enzymol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1146\/annurev.bi.64.070195.003253","article-title":"Interfacial enzymology of glycerolipid hydrolases: Lessons from secreted phospholipases A2","volume":"64","author":"Gelb","year":"1995","journal-title":"Annu. Rev. Biochem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1044","DOI":"10.1039\/C6NP00021E","article-title":"Recent advances in research on lignans and neolignans","volume":"33","author":"Teponno","year":"2016","journal-title":"Nat. Prod. Rep."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"110129","DOI":"10.1016\/j.cbi.2022.110129","article-title":"New derivatives from dehydrodieugenol B and its methyl ether displayed high anti-Trypanosoma cruzi activity and cause depolarization of the plasma membrane and collapse the mitochondrial membrane potential","volume":"366","author":"Galhardo","year":"2022","journal-title":"Chem.-Biol. Interact."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.cbi.2017.08.017","article-title":"Neolignans from leaves of Nectandra leucantha (Lauraceae) display in vitro antitrypanosomal activity via plasma membrane and mitochondrial damages","volume":"277","author":"Grecco","year":"2017","journal-title":"Chem.-Biol. Interact."},{"key":"ref_11","first-page":"1373","article-title":"Phospholipase A2 regulation of arachidonic acid mobilization","volume":"1761","author":"Balsinde","year":"2002","journal-title":"FEBS Lett."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2282","DOI":"10.1021\/acs.jnatprod.1c00386","article-title":"Effects of Eugenol and Dehydrodieugenol B from Nectandra leucantha against Lipopolysaccharide (LPS)-Induced Experimental Acute Lung Inflammation","volume":"84","author":"Pinheiro","year":"2021","journal-title":"J. Nat. Prod."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1128\/aac.00831-24","article-title":"Synthesis of a dehydrodieugenol B derivative as a lead compound for visceral leishmaniasis-mechanism of action and in vivo pharmacokinetic studies","volume":"68","author":"Amaral","year":"2024","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2872","DOI":"10.1021\/acsinfecdis.0c00523","article-title":"Structure-activity relationships of dehydrodieugenol derivatives against Trypanosoma cruzi","volume":"6","author":"Sear","year":"2020","journal-title":"ACS Infect. Dis."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.biochi.2012.09.007","article-title":"Emerging roles of secreted phospholipase A2 enzymes: An update","volume":"95","author":"Murakami","year":"2013","journal-title":"Biochimie"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1038\/nature01321","article-title":"The inflammatory reflex","volume":"420","author":"Tracey","year":"2002","journal-title":"Nature"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"17203","DOI":"10.1038\/s41598-019-53755-5","article-title":"Structural basis for phospholipase A2-like toxin inhibition by the synthetic compound Varespladib (LY315920)","volume":"9","author":"Salvador","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"56617","DOI":"10.1021\/acsomega.5c08750","article-title":"NSAIDs beyond COX: In Silico and In Vitro Insights into Acetylcholinesterase Modulation","volume":"10","author":"Roggero","year":"2025","journal-title":"ACS Omega"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"dos Santos Junior, A.B., Tamayose, C.I., Ferreira, M.J.P., Belchor, M.N., Costa, C.R.C., de Oliveira, M.A., and Toyama, M.H. (2020). Bioaffinity Fishing Procedure Using Secretory Phospholipase A2 for Screening for Bioactive Components: Modulation of Pharmacological Effect Induced by sPLA2 from Crotalus durissus terrificus by Hispidulin from Moquiniastrum floribundum. Molecules, 25.","DOI":"10.3390\/molecules25020282"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.phymed.2016.11.015","article-title":"Antitrypanosomal activity and evaluation of the mechanism of action of dehydrodieugenol isolated from Nectandra leucantha (Lauraceae) and its methylated derivative against Trypanosoma cruzi","volume":"24","author":"Grecco","year":"2017","journal-title":"Phytomedicine"}],"container-title":["Drugs and Drug Candidates"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2813-2998\/5\/1\/20\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,5]],"date-time":"2026-03-05T05:27:17Z","timestamp":1772688437000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2813-2998\/5\/1\/20"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,3]]},"references-count":20,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,3]]}},"alternative-id":["ddc5010020"],"URL":"https:\/\/doi.org\/10.3390\/ddc5010020","relation":{},"ISSN":["2813-2998"],"issn-type":[{"value":"2813-2998","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,3]]}}}