{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T05:54:27Z","timestamp":1790747667247,"version":"4.1.0"},"reference-count":59,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:00:00Z","timestamp":1790726400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>\n                    Leishmaniasis is a neglected tropical disease with a devastating global impact. The current medications on the market for treating this protozoan parasitic infection are insufficient to fit the global need, with long durations of therapy, growing resistance rates, and severe adverse effects. This investigation aims to characterize an antileishmanial structure-activity relationship for the natural product eugenol. With\n                    <jats:italic>Leishmania donovani<\/jats:italic>\n                    as a model, a series of dose-response curves were performed against eugenol and several of its structural analogs. The same set of compounds was tested against the human monocyte cell THP-1 to characterize their selective toxicity. Subsequently, the pharmacokinetic parameters of the tested compounds were estimated using the\n                    <jats:italic>in silico<\/jats:italic>\n                    modelling software, Percepta\u00ae. Eugenol and its analogs demonstrated varying levels of antileishmanial potency, with 4-allylphenol (chavicol) as the most potent compound tested and with the most promising selectivity index. In comparing the potencies and structures of the compounds tested, the data suggests that the para-substituted allyl tail and the phenolic group are important to conferring potency, while the ortho-methoxy substitutions decreased potency. Furthermore, the pharmacokinetic properties of these compounds were predicted to closely resemble eugenol with little risk of cytochrome P450 (CYP) interactions. While more testing is needed to confirm the mechanisms and safety of these compounds, these results suggest eugenol analogs show promise as future antileishmanial therapies.\n                  <\/jats:p>","DOI":"10.3389\/fphar.2026.1923146","type":"journal-article","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T04:54:46Z","timestamp":1790744086000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Mapping the antileishmanial structure-activity relationship of eugenol"],"prefix":"10.3389","volume":"17","author":[{"given":"Lucas","family":"Daut","sequence":"first","affiliation":[{"name":"Pharmaceutical Sciences Department, Pacific University School of Pharmacy","place":["Hillsboro, OR, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Taylor","sequence":"additional","affiliation":[{"name":"Pharmaceutical Sciences Department, Pacific University School of Pharmacy","place":["Hillsboro, OR, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicola S.","family":"Carter","sequence":"additional","affiliation":[{"name":"Pharmaceutical Sciences Department, Pacific University School of Pharmacy","place":["Hillsboro, OR, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brendan D.","family":"Stamper","sequence":"additional","affiliation":[{"name":"Pharmaceutical Sciences Department, Pacific University School of Pharmacy","place":["Hillsboro, OR, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,30]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"e35671","DOI":"10.1371\/journal.pone.0035671","article-title":"Leishmaniasis worldwide and global estimates of its incidence","volume":"7","author":"Alvar","year":"2012","journal-title":"PLoS One"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1344","DOI":"10.1039\/d3md00081h","article-title":"Biological activity and structure-activity relationship of dehydrodieugenol B analogues against visceral leishmaniasis","volume":"14","author":"Amaral","year":"2023","journal-title":"RSC Med. Chem."},{"key":"B3","doi-asserted-by":"publisher","first-page":"107535","DOI":"10.1016\/j.micpath.2025.107535","article-title":"Comprehensive insights into leishmaniasis: from etiopathogenesis to a novel therapeutic approach","volume":"204","author":"Ansari","year":"2025","journal-title":"Microb. Pathog"},{"key":"B4","doi-asserted-by":"publisher","first-page":"113409","DOI":"10.1016\/j.fct.2022.113409","article-title":"RIFM fragrance ingredient safety assessment,4-allylphenol, CAS registry number 501-92-8","volume":"169","author":"Api","year":"2022","journal-title":"Food Chem. Toxicol. An Int. J. Publ. Br. Industrial Biol. Res. Assoc."},{"key":"B5","doi-asserted-by":"publisher","first-page":"e202","DOI":"10.1093\/cid\/ciw670","article-title":"Diagnosis and treatment of leishmaniasis: Clinical practice guidelines by the infectious diseases society of America (IDSA) and the American society of tropical medicine and hygiene (ASTMH)","volume":"63","author":"Aronson","year":"2016","journal-title":"Clin. Infect. Dis. An Official Publ. Infect. Dis. Soc. Am."},{"key":"B6","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1038\/s41573-020-00114-z","article-title":"Natural products in drug discovery: advances and opportunities","volume":"20","author":"Atanasov","year":"2021","journal-title":"Nat. Rev. Drug Discov."},{"key":"B7","doi-asserted-by":"publisher","first-page":"190","DOI":"10.3390\/toxics13030190","article-title":"The role of oxidative stress in the pathogenesis and treatment of leishmaniasis: impact on drug toxicity and therapeutic potential of natural products","volume":"13","author":"Br\u00edgido","year":"2025","journal-title":"Toxics"},{"key":"B8","doi-asserted-by":"publisher","first-page":"951","DOI":"10.1016\/S0140-6736(18)31204-2","article-title":"Seminar Leishmaniasis","volume":"392","author":"Burza","year":"2018","journal-title":"Lancet"},{"key":"B9","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1186\/s13071-025-07105-2","article-title":"Insights on genomic profiles of drug resistance and virulence in a cohort of leishmania infantum isolates from the mediterranean area","volume":"19","author":"Carrasco-Martin","year":"2025","journal-title":"Parasites and Vectors"},{"key":"B10","doi-asserted-by":"publisher","first-page":"267","DOI":"10.3390\/microorganisms9020267","article-title":"Natural products that target the arginase in leishmania parasites hold therapeutic promise","volume":"9","author":"Carter","year":"2021","journal-title":"Microorganisms"},{"key":"B11","doi-asserted-by":"publisher","first-page":"155301","DOI":"10.1016\/j.cyto.2020.155301","article-title":"Oral administration of eugenol oleate cures experimental visceral leishmaniasis through cytokines abundance","volume":"145","author":"Charan Raja","year":"2021","journal-title":"Cytokine"},{"key":"B12","doi-asserted-by":"publisher","first-page":"54","DOI":"10.3390\/tropicalmed7040054","article-title":"Immune responses in leishmaniasis: an overview","volume":"7","author":"Costa-da-Silva","year":"2022","journal-title":"Trop. Med. Infect. Dis."},{"key":"B13","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1186\/s13065-018-0407-4","article-title":"Eugenol derivatives: synthesis, characterization, and evaluation of antibacterial and antioxidant activities","volume":"12","author":"da Silva","year":"2018","journal-title":"Chem. Central J."},{"key":"B14","doi-asserted-by":"publisher","first-page":"6250","DOI":"10.1016\/j.bmc.2014.08.020","article-title":"Thymol and eugenol derivatives as potential antileishmanial agents","volume":"22","author":"de Morais","year":"2014","journal-title":"Bioorg. and Med. Chem."},{"key":"B15","doi-asserted-by":"publisher","first-page":"335","DOI":"10.1007\/s00436-018-6157-3","article-title":"Berberine chloride mediates its antileishmanial activity by inhibiting leishmania mitochondria","volume":"118","author":"De Sarkar","year":"2019","journal-title":"Parasitol. Res."},{"key":"B16","doi-asserted-by":"publisher","first-page":"2081","DOI":"10.4049\/jimmunol.117.6.2081","article-title":"Antibody-induced modulation of Leishmania donovani surface membrane antigens","volume":"117","author":"Dwyer","year":"1976","journal-title":"J. Immunology"},{"key":"B17","doi-asserted-by":"publisher","first-page":"e15582","DOI":"10.7717\/peerj.15582","article-title":"Self-reported depression and anxiety rates among females with cutaneous leishmaniasis in hubuna, Saudi Arabia","volume":"11","author":"Elfaki","year":"2023","journal-title":"PeerJ"},{"key":"B18","doi-asserted-by":"publisher","first-page":"1225","DOI":"10.1093\/ced\/llaf548","article-title":"Cutaneous leishmaniasis: etiopathogenesis, epidemiology, clinical features, management, and research gaps","volume":"51","author":"Enbiale","year":"2025","journal-title":"Clin. Exp. Dermatology"},{"key":"B19","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1007\/978-1-60761-411-1_4","article-title":"Identification of ROS using oxidized DCFDA and flow-cytometry","volume":"594","author":"Eruslanov","year":"2010","journal-title":"Methods Mol. Biol. Clift. N.J."},{"key":"B20","doi-asserted-by":"publisher","first-page":"209","DOI":"10.3109\/00498259009047156","article-title":"The metabolism of eugenol in man","volume":"20","author":"Fischer","year":"1990","journal-title":"Xenobiotica; Fate Foreign Compd. Biol. Syst."},{"key":"B21","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1016\/s0166-6851(03)00142-7","article-title":"An in vitro system for developmental and genetic studies of Leishmania donovani phosphoglycans","volume":"130","author":"Goyard","year":"2003","journal-title":"Mol. Biochem. Parasitol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"3871","DOI":"10.3390\/molecules28093871","article-title":"The antileishmanial activity of eugenol associated with lipid storage reduction rather than membrane properties alterations","volume":"28","author":"Hughes","year":"2023","journal-title":"Mol. (Basel, Switzerland)"},{"key":"B23","doi-asserted-by":"publisher","first-page":"e0005011","DOI":"10.1371\/journal.pntd.0005011","article-title":"Immunotherapeutic potential of eugenol emulsion in experimental visceral leishmaniasis","volume":"10","author":"Islamuddin","year":"2016","journal-title":"PLoS Neglected Trop. Dis."},{"key":"B24","doi-asserted-by":"publisher","first-page":"137","DOI":"10.3390\/pathogens14020137","article-title":"Putrescine depletion in Leishmania donovani parasites causes immediate proliferation arrest followed by an apoptosis-like cell death","volume":"14","author":"Johnston","year":"2025","journal-title":"Pathog. (Basel, Switzerland)"},{"key":"B25","doi-asserted-by":"publisher","first-page":"e1800163","DOI":"10.1002\/minf.201800163","article-title":"Predicting pKa for small molecules on public and In-house datasets using fast prediction methods combined with data fusion","volume":"38","author":"Kalliokoski","year":"2019","journal-title":"Mol. Inf."},{"key":"B26","doi-asserted-by":"publisher","first-page":"107291","DOI":"10.1016\/j.intimp.2020.107291","article-title":"Synergic effect of eugenol oleate with amphotericin B augments anti-leishmanial immune response in experimental visceral leishmaniasis in vitro and in vivo","volume":"91","author":"Kar","year":"2021","journal-title":"Int. Immunopharmacol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"751","DOI":"10.1038\/nrd4683","article-title":"Hit and lead criteria in drug discovery for infectious diseases of the developing world","volume":"14","author":"Katsuno","year":"2015","journal-title":"Nat. Rev. Drug Discov."},{"key":"B28","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/978-3-030-89873-1_1","article-title":"Antimalarial natural products","volume":"117","author":"Kingston","year":"2022","journal-title":"Prog. Chem. Org. Nat. Prod."},{"key":"B29","doi-asserted-by":"publisher","first-page":"4125","DOI":"10.3390\/molecules25184125","article-title":"Thymol and thyme essential oil-new insights into selected therapeutic applications","volume":"25","author":"Kowalczyk","year":"2020","journal-title":"Mol. (Basel, Switzerland)"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1101\/pdb.prot095497","article-title":"Analysis of cell viability by the lactate dehydrogenase assay","volume":"2018","author":"Kumar","year":"2018","journal-title":"Cold Spring Harb. Protoc."},{"key":"B31","doi-asserted-by":"publisher","first-page":"1071","DOI":"10.3390\/molecules22071071","article-title":"In vitro anti-leishmanial activity of essential oils extracted from Vietnamese plants","volume":"22","author":"Le","year":"2017","journal-title":"Mol. (Basel, Switzerland)"},{"key":"B32","doi-asserted-by":"publisher","first-page":"e818","DOI":"10.1371\/journal.pntd.0000818","article-title":"Cost-effectiveness analysis of combination therapies for visceral leishmaniasis in the Indian subcontinent","volume":"4","author":"Meheus","year":"2010","journal-title":"PLOS Neglected Trop. Dis."},{"key":"B33","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1016\/s1383-5769(99)00020-3","article-title":"A simple colorimetric method to screen drug cytotoxicity against leishmania using the dye alamar blue","volume":"48","author":"Mikus","year":"2000","journal-title":"Parasitol. Int."},{"key":"B34","doi-asserted-by":"publisher","first-page":"1058","DOI":"10.1099\/jmm.0.009290-0","article-title":"Pro-apoptotic effect of the landrace Bangla Mahoba of Piper betle on Leishmania donovani may be due to the high content of eugenol","volume":"58","author":"Misra","year":"2009","journal-title":"J. Med. Microbiol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"151","DOI":"10.4103\/0974-777X.62883","article-title":"Treatment of visceral leishmaniasis","volume":"2","author":"Moore","year":"2010","journal-title":"J. Glob. Infect. Dis."},{"key":"B36","first-page":"341","article-title":"The radical scavenging activity and cytotoxicity of resveratrol, orcinol and 4-Allylphenol and their inhibitory effects on Cox-2 gene expression and Nf-\u03bab activation in RAW264.7 cells stimulated with porphyromonas gingivalis-fimbriae","volume":"29","author":"Murakami","year":"2015","journal-title":"Vivo (Athens, Greece)"},{"key":"B37","doi-asserted-by":"publisher","first-page":"3453","DOI":"10.3390\/molecules27113453","article-title":"Concentration dependence of Anti- and pro-oxidant activity of polyphenols as evaluated with a light-emitting Fe2+-Egta-H2O2 system","volume":"27","author":"Nowak","year":"2022","journal-title":"Mol. (Basel, Switzerland)"},{"key":"B38","doi-asserted-by":"publisher","first-page":"e0285663","DOI":"10.1371\/journal.pone.0285663","article-title":"The stigma associated with cutaneous leishmaniasis (CL) and mucocutaneous leishmaniasis (MCL): a protocol for a systematic review","volume":"18","author":"Nuwangi","year":"2023","journal-title":"PloS One"},{"key":"B39","doi-asserted-by":"publisher","first-page":"e0013144","DOI":"10.1371\/journal.pntd.0013144","article-title":"Direct sequencing of Leishmania donovani from patients in Garissa County, Northern Kenya, reveals a newly emerging intra-specific hybrid genotype","volume":"20","author":"Omwenga","year":"2026","journal-title":"PLOS Neglected Trop. Dis."},{"key":"B40","doi-asserted-by":"publisher","first-page":"1","DOI":"10.22099\/IJVR.2015.2917","article-title":"Plant-derived compounds in treatment of leishmaniasis","volume":"16","author":"Oryan","year":"2015","journal-title":"Iran. J. Veterinary Res."},{"key":"B41","doi-asserted-by":"publisher","first-page":"925","DOI":"10.1016\/j.apjtm.2016.06.021","article-title":"Worldwide risk factors in leishmaniasis","volume":"9","author":"Oryan","year":"2016","journal-title":"Asian Pac. J. Trop. Med."},{"key":"B42","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1038\/s41572-025-00663-w","article-title":"Leishmaniasis","volume":"11","author":"Pareyn","year":"2025","journal-title":"Nat. Reviews. Dis. Primers"},{"key":"B43","first-page":"749","article-title":"IARC monographs on the evaluation of carcinogenic risks to humans","volume":"71","year":"1999"},{"key":"B44","doi-asserted-by":"publisher","first-page":"1999","DOI":"10.1177\/1934578X1000501236","article-title":"Eugenol: a natural compound with versatile pharmacological actions","volume":"5","author":"Pramod","year":"2010","journal-title":"Nat. Product. Commun."},{"key":"B45","doi-asserted-by":"publisher","first-page":"268","DOI":"10.3390\/cancers15010268","article-title":"Novel strategies for the bioavailability augmentation and efficacy improvement of natural products in oral cancer","volume":"15","author":"Sachdeva","year":"2022","journal-title":"Cancers"},{"key":"B46","doi-asserted-by":"publisher","first-page":"155640","DOI":"10.1016\/j.phymed.2024.155640","article-title":"Natural endoperoxides as promising anti-leishmanials","volume":"129","author":"Sarkar","year":"2024","journal-title":"Phytomedicine Int. J. Phytotherapy Phytopharm."},{"key":"B47","doi-asserted-by":"publisher","first-page":"1","DOI":"10.4314\/ajtcam.v8i1.60483","article-title":"Extraction, isolation and characterization of bioactive compounds from plants\u2019 extracts","volume":"8","author":"Sasidharan","year":"2011","journal-title":"Afr. J. Traditional, Complementary, Altern. Med. AJTCAM"},{"key":"B48","doi-asserted-by":"publisher","first-page":"73","DOI":"10.14715\/cmb\/2017.63.6.15","article-title":"Pharmacological activities of cinnamaldehyde and eugenol: Antioxidant, cytotoxic and anti-leishmanial studies","volume":"63","author":"Sharma","year":"2017","journal-title":"Cell. Mol. Biol. (Noisy-Le-Grand, France)"},{"key":"B49","doi-asserted-by":"publisher","first-page":"2190","DOI":"10.3390\/nu12082190","article-title":"Natural sources, pharmacokinetics, biological activities and health benefits of hydroxycinnamic acids and their metabolites","volume":"12","author":"Sova","year":"2020","journal-title":"Nutrients"},{"key":"B50","doi-asserted-by":"publisher","first-page":"49","DOI":"10.14573\/altex.2412061","article-title":"Estimation of bioavailable concentration of endogenously formed N-nitrosamines by physiologically based kinetic modelling","volume":"43","author":"Spaenig","year":"2026","journal-title":"Altern. Animal Exp."},{"key":"B51","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/S1011-1344(97)00087-0","article-title":"Photosensitizing properties of quinine and synthetic antimalarials","volume":"42","author":"Spikes","year":"1998","journal-title":"J. Photochem. Photobiol. B, Biol."},{"key":"B52","doi-asserted-by":"publisher","first-page":"1104","DOI":"10.1086\/318121","article-title":"Failure of pentavalent antimony in visceral leishmaniasis in India: report from the center of the Indian epidemic","volume":"31","author":"Sundar","year":"2000","journal-title":"Clin. Infect. Dis. An Official Publ. Infect. Dis. Soc. Am."},{"key":"B53","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1080\/14787210.2019.1555471","article-title":"Understanding the economic impact of leishmaniasis on households in endemic countries: a systematic review","volume":"17","author":"Sunyoto","year":"2019","journal-title":"Expert Rev. Anti-infective Ther."},{"key":"B54","doi-asserted-by":"publisher","first-page":"S4248","DOI":"10.4103\/jpbs.jpbs_1250_24","article-title":"Unlocking the therapeutic benefits of Artemisia annua: a comprehensive overview of its medicinal properties","volume":"16","author":"Swamikannu","year":"2024","journal-title":"J. Pharm. and Bioallied Sci."},{"key":"B55","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1016\/s0065-308x(01)50032-9","article-title":"Antiparasitic properties of medicinal plants and other naturally occurring products","volume":"50","author":"Tagboto","year":"2001","journal-title":"Adv. Parasitol."},{"key":"B56","doi-asserted-by":"publisher","first-page":"1804","DOI":"10.2174\/1568026621666210701141433","article-title":"Eugenol as a potential drug candidate: a review","volume":"21","author":"Taleuzzaman","year":"2021","journal-title":"Curr. Top. Med. Chem."},{"key":"B57","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1002\/ijc.2910260208","article-title":"Establishment and characterization of a human acute monocytic leukemia cell line (THP-1)","volume":"26","author":"Tsuchiya","year":"1980","journal-title":"Int. Journal Cancer"},{"key":"B58","doi-asserted-by":"publisher","first-page":"e284742","DOI":"10.1590\/1519-6984.284742","article-title":"Epidemiological analysis of leishmaniasis prevalence in Pakistan during 2016-2023","volume":"84","author":"Uppal","year":"2025","journal-title":"Braz. J. Biol. = Revista Brasleira de Biol."},{"key":"B59","doi-asserted-by":"publisher","first-page":"39925","DOI":"10.1074\/jbc.M405635200","article-title":"Dual action of antimonial drugs on thiol redox metabolism in the human pathogen Leishmania donovani","volume":"279","author":"Wyllie","year":"2004","journal-title":"J. Biol. Chem."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1923146\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T04:54:49Z","timestamp":1790744089000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1923146\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,30]]},"references-count":59,"alternative-id":["10.3389\/fphar.2026.1923146"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2026.1923146","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,30]]},"article-number":"1923146"}}