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Despite its growing medical importance, therapeutic options for angiostrongyliasis remain limited, highlighting the need for new anthelmintic agents. Methods: The anthelmintic activity of andrographolide, a diterpene lactone isolated from Cymbopogon schoenanthus, was evaluated against first-stage (L1) larvae, infective third-stage (L3) larvae, and adult worms of A. cantonensis using motility-based phenotypic assays. Toxicity was assessed in mammalian cell models and Caenorhabditis elegans, and drug-likeness and ADMET properties were evaluated using in silico approaches. Results: Andrographolide exhibited concentration-dependent activity across all developmental stages, with EC50 values of 12.5, 11.2, and 7.3 \u00b5M for L1, L3, and adult worms, respectively. These EC50 values were similar to those of albendazole, with no statistically significant differences detected for any developmental stage. No toxicity was detected at the highest concentrations tested in mammalian cell models (CC50 &gt; 500 \u00b5M) or C. elegans (LD50 &gt; 1000 \u00b5M), supporting a preliminary selectivity profile. The in silico analyses predicted compliance with major drug-likeness rules, absence of PAINS alerts, high gastrointestinal absorption, and low probabilities of hepatotoxicity, nephrotoxicity, and neurotoxicity. Conclusions: Andrographolide represents a promising in vitro anthelmintic hit against A. cantonensis and warrants further preclinical investigation.<\/jats:p>","DOI":"10.3390\/ph19091435","type":"journal-article","created":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T15:54:19Z","timestamp":1789055659000},"page":"1435","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Andrographolide as a Promising Diterpenoid Scaffold Against the Neurotropic Nematode Angiostrongylus cantonensis"],"prefix":"10.3390","volume":"19","author":[{"given":"Fabiana R. S.","family":"Tominaga","sequence":"first","affiliation":[{"name":"Research Center on Neglected Diseases, Brazil University, S\u00e3o Paulo 08230-030, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Davi","family":"Luna-Tavares","sequence":"additional","affiliation":[{"name":"Research Center on Neglected Diseases, Brazil University, S\u00e3o Paulo 08230-030, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-8829-7604","authenticated-orcid":false,"given":"Lucas","family":"Fukui-Silva","sequence":"additional","affiliation":[{"name":"Research Center on Neglected Diseases, Guarulhos University, Guarulhos 07023-070, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thain\u00e1 R.","family":"Teixeira","sequence":"additional","affiliation":[{"name":"Research Center on Neglected Diseases, Guarulhos University, Guarulhos 07023-070, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henrique","family":"Barbosa","sequence":"additional","affiliation":[{"name":"Center for Natural and Human Sciences, Federal University of ABC, S\u00e3o Paulo 09210-180, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1193-8374","authenticated-orcid":false,"given":"Jo\u00e3o Henrique G.","family":"Lago","sequence":"additional","affiliation":[{"name":"Center for Natural and Human Sciences, Federal University of ABC, S\u00e3o Paulo 09210-180, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josu\u00e9","family":"de Moraes","sequence":"additional","affiliation":[{"name":"Research Center on Neglected Diseases, Brazil University, S\u00e3o Paulo 08230-030, SP, Brazil"},{"name":"Research Center on Neglected Diseases, Guarulhos University, Guarulhos 07023-070, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"662","DOI":"10.1016\/j.pt.2026.03.008","article-title":"Angiostrongylus cantonensis (rat lungworm)","volume":"42","author":"Jones","year":"2026","journal-title":"Trends Parasitol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1186\/s13071-025-06790-3","article-title":"Insights into the biology of the rat lungworm, Angiostrongylus cantonensis","volume":"18","author":"Griffin","year":"2025","journal-title":"Parasites Vectors"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e00265-26","DOI":"10.1128\/msphere.00265-26","article-title":"Climate change and the emerging ecology of helminthiases: A One Health perspective integrating microbial and environmental drivers","volume":"11","year":"2026","journal-title":"mSphere"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2102","DOI":"10.1021\/acschemneuro.7b00335","article-title":"Angiostrongylus cantonensis: Agent of a Sometimes Fatal Globally Emerging Infectious Disease (Rat Lungworm Disease)","volume":"8","author":"Cowie","year":"2017","journal-title":"ACS Chem. 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