{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T20:44:57Z","timestamp":1791924297902,"version":"4.3.4"},"reference-count":29,"publisher":"American Chemical Society (ACS)","issue":"40","license":[{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003593","name":"Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico","doi-asserted-by":"publisher","award":["303820\/2023-3"],"award-info":[{"award-number":["303820\/2023-3"]}],"id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003593","name":"Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico","doi-asserted-by":"publisher","award":["307299\/2026-0"],"award-info":[{"award-number":["307299\/2026-0"]}],"id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001807","name":"Funda??o de Amparo ? Pesquisa do Estado de S?o Paulo","doi-asserted-by":"publisher","award":["2018\/18954-4"],"award-info":[{"award-number":["2018\/18954-4"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001807","name":"Funda??o de Amparo ? Pesquisa do Estado de S?o Paulo","doi-asserted-by":"publisher","award":["2020\/033995"],"award-info":[{"award-number":["2020\/033995"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001807","name":"Funda??o de Amparo ? Pesquisa do Estado de S?o Paulo","doi-asserted-by":"publisher","award":["2023\/18327-8"],"award-info":[{"award-number":["2023\/18327-8"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001807","name":"Funda??o de Amparo ? Pesquisa do Estado de S?o Paulo","doi-asserted-by":"publisher","award":["2024\/22547-6"],"award-info":[{"award-number":["2024\/22547-6"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001807","name":"Funda??o de Amparo ? Pesquisa do Estado de S?o Paulo","doi-asserted-by":"publisher","award":["2025\/26427-8"],"award-info":[{"award-number":["2025\/26427-8"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002322","name":"Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior","doi-asserted-by":"publisher","award":["88887.162302\/2025-00"],"award-info":[{"award-number":["88887.162302\/2025-00"]}],"id":[{"id":"10.13039\/501100002322","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,10,13]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Toxoplasma gondii is an obligate intracellular protozoan responsible for toxoplasmosis, a widespread parasitic disease that poses a serious health threat, especially to immunocompromised patients and pregnant women. Current therapeutic options remain unsatisfactory because they are associated with adverse effects and do not eliminate latent infections, emphasizing the need for new antitoxoplasmic agents. In the present study, the natural neolignan (\u2212)-licarin A (1), isolated from the Brazilian species Nectandra oppositifolia, together with three semisynthetic derivatives, 4-O-methyl (1a), 4-O-acetyl (1b), and 4-O-allyl (1c), were investigated for their in vitro activity against T. gondii tachyzoites. Antiparasitic activity (EC50) was determined using a \u03b2-galactosidase-based assay, while cytotoxicity (CC50) toward Human Foreskin Fibroblasts (HFF) was assessed by the resazurin assay. Among the tested compounds, derivative 1c exhibited the highest potency (EC50 = 3.49 \u03bcM) and lowest cytotoxicity (CC50 = 120.10 \u03bcM), resulting in the highest selectivity index (SI = 34.41). In silico ADMET analysis predicted favorable gastrointestinal absorption and blood\u2013brain barrier permeability for all licarin derivatives. Mechanistic assays demonstrated that licarin A derivatives 1a\u20131c did not compromise parasite plasma membrane integrity but significantly reduced mitochondrial membrane potential, supporting an intracellular mode of action. Further functional analyses revealed that compound 1c inhibited intracellular parasite proliferation in a concentration-dependent manner and maintained significant antiparasitic activity after drug removal only at the highest concentration tested, without affecting parasite invasion or intracellular replication following pretreatment of extracellular tachyzoites. Overall, these findings identify the 4-O-allyl derivative of licarin A as the most selective compound of this series and provide additional evidence that semisynthetic modification of the licarin scaffold represents a promising strategy for discovering new therapeutic candidates against T. gondii.<\/jats:p>","DOI":"10.1021\/acsomega.6c05944","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T05:05:54Z","timestamp":1790831154000},"page":"61199-61207","source":"Crossref","is-referenced-by-count":0,"title":["4-\n                    <i>O<\/i>\n                    -Allyl Derivative\nof Natural Licarin A Exhibits Selective\n                    <i>In Vitro<\/i>\n                    Activity\nagainst\n                    <i>Toxoplasma gondii<\/i>\n                    Tachyzoites"],"prefix":"10.1021","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1256-057X","authenticated-orcid":true,"given":"Gabriel Candido","family":"Moura","sequence":"first","affiliation":[{"name":"Faculdade de Medicina de Jundiai\u0301 , , , ,","place":["Jundiai\u0301, Sa\u0303o Paulo, Brazil, 13202-550"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie Ortega","family":"Alves","sequence":"additional","affiliation":[{"name":"Faculdade de Medicina de Jundiai\u0301 , , , ,","place":["Jundiai\u0301, Sa\u0303o Paulo, Brazil, 13202-550"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingrid","family":"de Oliveira Dias","sequence":"additional","affiliation":[{"name":"Faculdade de Medicina de Jundiai\u0301 , , , ,","place":["Jundiai\u0301, Sa\u0303o Paulo, Brazil, 13202-550"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9089-273X","authenticated-orcid":true,"given":"Joa\u0303o Paulo","family":"dos Santos Fernandes","sequence":"additional","affiliation":[{"name":"Universidade Federal de Sa\u0303o Paulo , , , ,","place":["Diadema, Sa\u0303o Paulo, Brazil, 09972-270"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"da Costa Trista\u0303o","sequence":"additional","affiliation":[{"name":"Federal University of the ABC , , , ,","place":["Santo Andre, Sa\u0303o Paulo, Brazil, 09210-580"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1193-8374","authenticated-orcid":true,"given":"Joa\u0303o Henrique Ghilardi","family":"Lago","sequence":"additional","affiliation":[{"name":"Federal University of the ABC , , , ,","place":["Santo Andre, Sa\u0303o Paulo, Brazil, 09210-580"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4418-0838","authenticated-orcid":true,"given":"Juliana Quero","family":"Reima\u0303o","sequence":"additional","affiliation":[{"name":"Faculdade de Medicina de Jundiai\u0301 , , , ,","place":["Jundiai\u0301, Sa\u0303o Paulo, Brazil, 13202-550"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,10,1]]},"reference":[{"issue":"2","key":"2026101315101096600_cit1","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1016\/j.ijpara.2020.11.001","article-title":"Control of Human Toxoplasmosis","volume":"51","author":"Smith","year":"2021","journal-title":"Int. J. Parasitol."},{"issue":"1","key":"2026101315101096600_cit2","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1080\/20477724.2022.2083977","article-title":"Cerebral Toxoplasmosis\nin HIV-Infected\nPatients: A Review","volume":"117","author":"Dian","year":"2023","journal-title":"Pathog. Global Health"},{"issue":"12","key":"2026101315101096600_cit3","doi-asserted-by":"publisher","first-page":"1406","DOI":"10.1017\/S0031182021001013","article-title":"Congenital Toxoplasmosis in Humans: An Update of Worldwide\nRate of Congenital Infections","volume":"148","author":"Dubey","year":"2021","journal-title":"Parasitology"},{"key":"2026101315101096600_cit4","doi-asserted-by":"publisher","first-page":"273","DOI":"10.2147\/DDDT.S60973","article-title":"Drugs in Development for Toxoplasmosis: Advances, Challenges,\nand Current Status","volume":"11","author":"Alday","year":"2017","journal-title":"Drug Des. Dev. Ther."},{"issue":"4","key":"2026101315101096600_cit5","doi-asserted-by":"publisher","DOI":"10.1128\/cmr.00057-17","article-title":"Treatment of Toxoplasmosis: Historical\nPerspective,\nAnimal Models, and Current Clinical Practice","volume":"31","author":"Dunay","year":"2018","journal-title":"Clin. Microbiol. Rev."},{"issue":"12","key":"2026101315101096600_cit6","doi-asserted-by":"publisher","DOI":"10.3390\/microorganisms9122531","article-title":"Toxoplasmosis: Current\nand Emerging\nParasite Druggable Targets","volume":"9","author":"Hajj","year":"2021","journal-title":"Microorganisms"},{"key":"2026101315101096600_cit7","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2021.691121","article-title":"Re-Envisioning Anti-Apicomplexan Parasite Drug Discovery\nApproaches","volume":"11","author":"Rangel","year":"2021","journal-title":"Front. Cell. Infect. Microbiol."},{"issue":"1","key":"2026101315101096600_cit8","doi-asserted-by":"publisher","DOI":"10.1038\/s44259-025-00119-x","article-title":"A Review\nof Natural Products as a Source of Next-Generation Drugs against Apicomplexan\nParasites","volume":"3","author":"Mao","year":"2025","journal-title":"npj Antimicrob. Resist."},{"issue":"24","key":"2026101315101096600_cit9","doi-asserted-by":"publisher","DOI":"10.3390\/ijms232415482","article-title":"Antioxidant,\nAnti-Inflammatory, Anti-Menopausal,\nand Anti-Cancer Effects of Lignans and Their Metabolites","volume":"23","author":"Jang","year":"2022","journal-title":"Int. J. Mol. Sci."},{"issue":"11","key":"2026101315101096600_cit10","doi-asserted-by":"publisher","DOI":"10.3390\/ph15111351","article-title":"Synthesis\nand Biological Activities of Dehydrodiisoeugenol: A Review","volume":"15","author":"Godi\u0301nez-Chaparro","year":"2022","journal-title":"Pharmaceuticals"},{"key":"2026101315101096600_cit11","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1016\/j.biochi.2022.12.018","article-title":"Lethal Action of Licarin A Derivatives\nin Leishmania (L.) Infantum: Imbalance of Calcium and Bioenergetic\nMetabolism","volume":"208","author":"de Castro Levatti","year":"2023","journal-title":"Biochimie"},{"issue":"1","key":"2026101315101096600_cit12","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-62352-w","article-title":"Improving the\nDrug-Likeness of Inspiring Natural Products - Evaluation of the Antiparasitic\nActivity against Trypanosoma cruzi through Semi-Synthetic\nand Simplified Analogues of Licarin A","volume":"10","author":"Morais","year":"2020","journal-title":"Sci.\nRep."},{"key":"2026101315101096600_cit13","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1590\/0001-3765201720160298","article-title":"Natural Compounds\nfrom Mexican Medicinal Plants as Potential Drug Leads for Anti-Tuberculosis\nDrugs","volume":"89","author":"Gomez-Cansino","year":"2017","journal-title":"An. Acad. Bras. Cie\u0302nc."},{"key":"2026101315101096600_cit14","doi-asserted-by":"publisher","DOI":"10.1016\/j.actatropica.2019.105248","article-title":"(\u00b1)-Licarin A and Its Semi-Synthetic Derivatives: In Vitro and in Silico Evaluation of Trypanocidal\nand Schistosomicidal Activities","volume":"202","author":"Meleti","year":"2020","journal-title":"Acta Trop."},{"key":"2026101315101096600_cit15","doi-asserted-by":"publisher","DOI":"10.1016\/j.tet.2024.134366","article-title":"Anthelmintic\nActivity of Selected\nNeolignans and Semisynthetic Derivatives from Styrax suberifolius","volume":"169","author":"Wijesekera","year":"2025","journal-title":"Tetrahedron"},{"issue":"1","key":"2026101315101096600_cit16","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-022-23110-2","article-title":"Neolignans\nIsolated from Saururus cernuus L. (Saururaceae)\nExhibit Efficacy against Schistosoma mansoni","volume":"12","author":"Brito","year":"2022","journal-title":"Sci. Rep."},{"key":"2026101315101096600_cit17","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1007\/978-3-030-64853-4_3","article-title":"Antileishmanial Activity\nof Lignans, Neolignans, and Other Plant Phenols","volume":"115","author":"Pospi\u0301s\u030cil","year":"2021","journal-title":"Prog. Chem. Org. Nat. Prod."},{"issue":"3","key":"2026101315101096600_cit18","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1016\/j.exppara.2009.11.007","article-title":"Neolignans from\nPlants in Northeastern Brazil (Lauraceae) with Activity against Trypanosoma cruzi","volume":"124","author":"Cabral","year":"2010","journal-title":"Exp. Parasitol."},{"issue":"9","key":"2026101315101096600_cit19","doi-asserted-by":"publisher","DOI":"10.1002\/cbdv.201700209","article-title":"Bioactive Neolignans\nand Other Compounds from Magnolia grandiflora L.: Isolation and Antiplasmodial Activity","volume":"14","author":"Latif","year":"2017","journal-title":"Chem. Biodiversity"},{"issue":"9","key":"2026101315101096600_cit20","doi-asserted-by":"publisher","first-page":"5154","DOI":"10.1002\/ptr.7184","article-title":"Licarin A, a Neolignan Isolated from Nectandra oppositifolia Nees & Mart. (Lauraceae),\nExhibited Moderate Preclinical Efficacy against Schistosoma mansoni Infection","volume":"35","author":"Mengarda","year":"2021","journal-title":"Phytother.\nRes."},{"issue":"11","key":"2026101315101096600_cit21","doi-asserted-by":"publisher","first-page":"1424","DOI":"10.1016\/j.phytochem.2011.04.007","article-title":"Schistosomicidal and Trypanocidal\nStructure\u2013Activity Relationships for (\u00b1)-Licarin A and\nIts (\u2212)- and (+)-Enantiomers","volume":"72","author":"Pereira","year":"2011","journal-title":"Phytochemistry"},{"issue":"2","key":"2026101315101096600_cit22","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1016\/j.exppara.2013.07.007","article-title":"Neolignan Licarin A Presents Effect\nagainst Leishmania (Leishmania) major Associated\nwith Immunomodulation in Vitro","volume":"135","author":"Ne\u0301ris","year":"2013","journal-title":"Exp. Parasitol."},{"key":"2026101315101096600_cit23","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.684393","article-title":"Licarin-B\nExhibits Activity Against\nthe Toxoplasma gondii RH Strain by\nDamaging Mitochondria and Activating Autophagy","volume":"9","author":"Zhang","year":"2021","journal-title":"Front. Cell Dev. Biol."},{"key":"2026101315101096600_cit24","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1016\/0378-1119(95)00786-5","article-title":"Escherichia coli beta-galactosidase\nas an in vitro and in vivo reporter enzyme and stable transfection\nmarker in the intracellular protozoan parasite Toxoplasma gondii","volume":"169","author":"Seeber","year":"1996","journal-title":"Gene"},{"key":"2026101315101096600_cit25","first-page":"99","article-title":"Assays for\nMonitoring Toxoplasma gondii Infectivity\nin the Laboratory Mouse","volume-title":"Methods Mol. Biol.","author":"Wang","year":"2020"},{"issue":"9","key":"2026101315101096600_cit26","doi-asserted-by":"publisher","first-page":"1849","DOI":"10.1128\/AAC.41.9.1849","article-title":"Use of Toxoplasma gondii Expressing Beta-Galactosidase for Colorimetric\nAssessment of Drug Activity in Vitro","volume":"41","author":"McFadden","year":"1997","journal-title":"Antimicrob.\nAgents Chemother."},{"issue":"28","key":"2026101315101096600_cit27","doi-asserted-by":"publisher","first-page":"31147","DOI":"10.1021\/acsomega.5c05130","article-title":"Phenotypic\nScreening of the MMV Global Health Priority\nBox Identifies Selective Compounds with Anti-Toxoplasma gondii Activity","volume":"10","author":"Moura","year":"2025","journal-title":"ACS Omega"},{"issue":"8","key":"2026101315101096600_cit28","doi-asserted-by":"publisher","DOI":"10.1007\/s00436-024-08318-7","article-title":"Assessment\nof Nebivolol Efficacy in Experimental Models of Toxoplasmosis: Insights\ninto Parasite Burden Reduction and Neuronal Protection","volume":"123","author":"da Silva Bellini Ramos","year":"2024","journal-title":"Parasitol. Res."},{"key":"2026101315101096600_cit29","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2025.1673462","article-title":"Novel Drug Candidates\nTargeting Toxoplasma gondii in Maternal\u2013Fetal\nInterface Models","volume":"16","author":"de Oliveira","year":"2025","journal-title":"Front. Pharmacol."}],"container-title":["ACS Omega"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acsomega.6c05944","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/acsodf\/article-pdf\/11\/40\/61199\/68721558\/acsomega.6c05944.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/acsodf\/article-pdf\/11\/40\/61199\/68721558\/acsomega.6c05944.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T19:50:20Z","timestamp":1791921020000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/acsodf\/article\/11\/40\/61199\/5443096\/4-O-Allyl-Derivative-of-Natural-Licarin-A-Exhibits"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,1]]},"references-count":29,"journal-issue":{"issue":"40","published-online":{"date-parts":[[2026,10,1]]},"published-print":{"date-parts":[[2026,10,13]]}},"URL":"https:\/\/doi.org\/10.1021\/acsomega.6c05944","relation":{},"ISSN":["2470-1343"],"issn-type":[{"value":"2470-1343","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,1]]}}}