Background: Marine macroalgae has been studied by our research group as alternative sources of bioactive compounds with promising antiparasitic activity, particularly against Schistosoma mansoni. Objectives: This study aimed to employ a metabolomics-based approach to identify anthelminthic active compounds from the macroalgae Laurencia aldingensis Saito and Womersley 1974 and Laurencia dendroidea J. Agardh 1852. Methods: The algae were extracted using a dichloromethane/methanol mixture, followed by liquid–liquid partitioning and sequential chromatographic fractionation using solvents of varying polarities. The resulting fractions were tested for biological activity against adult Schistosoma mansoni worms. Detailed chemical characterization of the extracts was conducted via HPLC-DAD-MS/MS, with subsequent data alignment and statistical analysis (Pearson correlation) to associate specific chemical compounds with the observed bioactivity. Results: Non-polar fractions (hexane and dichloromethane) exhibited significant anthelminthic activity, substantially reducing parasite viability and reproduction. Specific subfractions obtained from the dichloromethane fraction demonstrated notable activity. Metabolomic analysis revealed considerable chemical diversity, emphasizing the presence of bromophenols and halogenated sesquiterpenes, including potentially novel compounds with therapeutic potential against schistosomiasis. Conclusions: The metabolomics approach proved effective in identifying promising bioactive compounds from Laurencia spp. macroalgae with activity against S. mansoni.

Background/Objectives: Schistosomiasis, a parasitic disease caused by Schistosoma worms with freshwater snails as intermediate hosts, affects over 250 million people. The current control relies solely on praziquantel, which raises concerns on drug resistance and highlights the need for new therapeutic alternatives. Our bioprospection studies have focused on marine macroalgae as an unexplored source of antischistosomal metabolites with promising results. Guided by WHO recommendations to target both the parasite and its transmission vectors, this study aimed to investigate Ochtodes secundiramea to: (i) isolate active metabolites; (ii) evaluate the isolated compounds against adult worms and oviposition to identify leads for drug development; and (iii) perform an independent screening of their effects against the environmental transmission stages on cercariae and B. glabrata embryos. Methods: A dichloromethane extract of O. secundiramea was submitted to an NMR–biomonitored guided fractionation against Schistosoma mansoni adult worms. Active fractions were further purified through HPLC and characterized by ¹H and ¹³C NMR spectroscopy to identify the isolated compounds. Results: Three halogenated monoterpenes were isolated: ochtodene 1 (4-bromo-1,6,8-trichloro-2,3-ochtodene), ochtodene 2 (2-chloro-1,6,8-tribromo-3,8-ochtodene), and the novel natural product ochtodene 3 [2,6-dibromo-4-(2-chloroethylidene)-1,1dimethylcyclohexane]. Ochtodene 1 was the primary active metabolite against Schistosoma mansoni adult worms, with IC₅₀/96 h values of 47.2 and 46.1 µM for male and female worms respectively, and totally suppressed egg laying with 60 µM, while showing no toxicity toward human fibroblasts. Notably, all metabolites, including the novel ochtodene 3, caused 100% mortality in cercariae and embryos at low concentrations. Conclusions: The discovery of the novel ochtodene 3 and the identification of distinct leads for host treatment and transmission elimination position O. secundiramea as a promising source for integrated schistosomiasis control.