Sakuranetin Reveals Potent, Stage-Dependent Anthelmintic Activity against Angiostrongylus cantonensis

Abstract Angiostrongylus cantonensis, the leading cause of human eosinophilic meningitis, is an emerging zoonotic parasite of growing public health concern. Current therapeutic options show limited efficacy, particularly against larval stages, underscoring the need for new anthelmintic agents. Natural products derived from Brazilian biodiversity represent a promising source for discovery of new bioactive compounds. In this study, we evaluated the anthelmintic activity of sakuranetin, a naturally occurring flavanone from Brazilian plant Baccharis lateralis (Asteraceae), against first-stage (L1) and third-stage (L3) larvae of A. cantonensis, along with its safety profile. Sakuranetin exhibited stage-dependent activity, being more active against L1 larvae (EC50 = 8.1 μM) than against L3 (EC50 = 62.7 μM), outperforming albendazole (∼15 μM) and showing comparable activity to pyrantel pamoate (∼10 μM) in L1. No cytotoxic effects were observed in mammalian cell lines up to 500 μM, resulting in high selectivity indices, and no toxicity was detected in Caenorhabditis elegans. Morphological and morphometric analyses revealed pronounced phenotypic alterations, including body contraction and significant reduction in larval length. Fluorescence microscopy revealed a stage-dependent increase in propidium iodide staining, with L1 larvae showing markedly higher fluorescence than L3, consistent with greater susceptibility and reduced viability. In silico analysis did not identify relevant alerts for hepatotoxicity or neurotoxicity. Collectively, these findings demonstrate that sakuranetin exhibits stage-dependent anthelmintic activity against A. cantonensis, with low toxicity in the experimental models evaluated and favorable predictive toxicological properties, supporting its potential as a candidate for antiparasitic drug development.