Isolamento e caracterização e substâncias naturais de Pothomorphe umbellata, Acmella oleracea e Aesculus hippocastanum visando novos tratamentos para esquistossomose

Abstract

The disease caused by infection with the parasite Schistosoma mansoni, schistosomiasis, remains a concerning public health issue globally and in Brazil, being listed among the Neglected Tropical Diseases (NTDs) by the World Health Organization (WHO). In Brazil, one of the regions most affected by schistosomiasis is the state of Minas Gerais (MG). WHO recommends the treatment for schistosomiasis with a single drug, praziquantel (PZQ), which acts only on the adult stage of S. mansoni, proving ineffective in the early stages of infection in juvenile parasites, with reports of resistance in certain parasite strains. In this context, the exploration of new schistosomicidal drugs becomes imperative. In traditional medicine, there are reports of the use of various plants with antiparasitic properties, including Acmella oleracea, Pothomorphe umbellata, and Aesculus hippocastanum. These plants have diverse biological activities described in the literature, such as antimalarial, anti-helminthic, anti-inflammatory, among others. The overarching goal of this study was to assess the schistosomicidal activity of extracts from A. oleracea (AoE), P. umbellata (PuH), and A. hippocastanum (HCSE), as well as their primary secondary metabolites: spilanthol (SPL), 4-nerolidilcatecol (4-NC), and Escin (ESC). Additionally, the extracts were analyzed by HPLC-DAD and UHPLC-ESI-QTOF-MS. SPL and 4-NC metabolites were isolated and characterized by HPLC-DAD, UHPLC-ESIQTOF-MS, and 1H and 13C NMR. ESC was commercially acquired. The extracts and their metabolites were evaluated in vitro and in vivo against adult S. mansoni worms, with 4-NC also tested against juvenile worms. The comprehensive results of this study highlight the remarkable schistosomicidal activity of the hexane extract from Pothomorphe umbellata roots (PuH), the ethanolic extract from Acmella oleracea inflorescences (AoE), and the standardized extract from Aesculus hippocastanum seeds (HCSE), along with their secondary metabolites: 4- nerolidilcatecol (4-NC), spilanthol (SPL), and escin (ESC), respectively. UHPLC-ESI-QTOFMS analysis revealed the presence of 4-NC, peltatol A, and peltatol B or C in the PuH extract. In the AoE extract, 14 alkylamides, including SPL, were annotated through UHPLC-ESIQTOF-MS analysis. In the HCSE extract, 13 saponins were annotated through UHPLC-ESIQTOF-MS analysis. The concentration of 4-NC in PuH was approximately 80%, and the concentration of SPL in AoE was approximately 85%. The extracts and isolated compounds were assessed in in vitro assays against S. mansoni, demonstrating significant activities without toxicity to mammalian cells or C. elegans. In vivo analyses against S. mansoni revealed reductions of approximately 50% for 4-NC, 33% for SPL, 28% for AoE, 70% for ESC, and 28% for HCSE in total parasite burden. Regarding egg quantity, reductions of approximately XII 52% for 4-NC, 63% for SPL, 46% for AoE, 81% for ESC, and 46% for HCSE were observed. As for hepatosplenomegaly, oral administration of samples (400 mg∙kg-1 ) reduced the liver and spleen weights of treated animals by percentages ranging from 16% to 37% for 4-NC, SPL, AoE, and ESC. Furthermore, 4-NC demonstrated in vivo efficacy against young parasites (prepatent infection) of S. mansoni, unlike PZQ, which exhibits low activity in this phase of infection. In relation to pre-patent infection, 4-NC showed significant results, while ESC and HCSE were inactive, requiring additional studies for SPL and AoE. These findings open new perspectives for future evaluations with natural products, suggesting the potential clinical repurposing of herbal remedies already commercialized against S. mansoni.