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There is an urgent need to discover and develop new anthelmintics for the treatment of parasitic nematodes of veterinary importance to circumvent challenges linked to drug resistant parasites. Being one of the most diverse natural ecosystems, the marine environment represents a rich resource of novel chemical entities. This study investigated 2000 extracts from marine invertebrates, collected from Australian waters, for anthelmintic activity. Using a well-established in vitro bioassay, these extracts were screened for nematocidal activity against Haemonchus contortus -a socioeconomically important parasitic nematode of livestock animals. Extracts (designated Mu -1, Ha -1 and Ha -2) from two marine sponges ( Monanchora unguiculata and Haliclona sp.) each significantly affected larvae of H. contortus . Individual extracts displayed a dose-dependent inhibition of both the motility of exsheathed third-stage larvae (xL3s) and the development of xL3s to fourth-stage larvae (L4s). Active fractions in each of the three extracts were identified using bioassay-guided fractionation. From the active fractions from Monanchora unguiculata , a known pentacyclic guanidine alkaloid, fromiamycalin ( 1 ), was purified. This alkaloid was shown to be a moderately potent inhibitor of L4 development (half-maximum inhibitory concentration (IC 50 ) = 26.6 ± 0.74 µM) and L4 motility (IC 50 = 39.4 ± 4.83 µM), although it had a relatively low potency at inhibiting of xL3 motility (IC 50 ≥ 100 µM). Investigation of the active fractions from the two Haliclona collections led to identification of a mixture of amino alcohol lipids, and, subsequently, a known natural product halaminol A ( 5 ). Anthelmintic profiling showed that 5 had limited potency at inhibiting larval development and motility. These data indicate that fromiamycalin, other related pentacyclic guanidine alkaloids and/or halaminols could have potential as anthelmintics following future medicinal chemistry efforts., Competing Interests: The authors declare no conflicts of interest. Funding bodies played no role in the design of the study, collection, analysis or interpretation of data, or in the writing of the manuscript or in the decision to publish the results.