Antischistosomal Properties of Sclareol and Its Heck-Coupled Derivatives: Design, Synthesis, Biological Evaluation, and Untargeted Metabolomics

Abstract

Sclareol, a plant-derived diterpenoid widely used as a fragrance and flavoring substance, is well-known for its promising antimicrobial and anticancer properties. However, its activity on helminth parasites has not been previously reported. Here, we show that sclareol is active against larval (IC50 ≈ 13 μM), juvenile (IC50 = 5.0 μM), and adult (IC50 = 19.3 μM) stages of Schistosoma mansoni, a parasitic trematode responsible for the neglected tropical disease schistosomiasis. Microwave-assisted synthesis of Heck-coupled derivatives improved activity, with the substituents choice guided by the Matsy decision tree. The most active derivative 12 showed improved potency and selectivity on larval (IC50 ≈ 2.2 μM, selectivity index (SI) ≈ 22 in comparison to HepG2 cells), juvenile (IC50 = 1.7 μM, SI = 28.8), and adult schistosomes (IC50 = 9.4 μM, SI = 5.2). Scanning electron microscopy studies revealed that compound 12 induced blebbing of the adult worm surface at sublethal concentration (12.5 μM); moreover, the compound inhibited egg production at the lowest concentration tested (3.13 μM). The observed phenotype and data obtained by untargeted metabolomics suggested that compound 12 affects membrane lipid homeostasis by interfering with arachidonic acid metabolism. The same methodology applied to praziquantel (PZQ)-treated worms revealed sugar metabolism alterations that could be ascribed to the previously reported action of PZQ on serotonin signaling and/or effects on glycolysis. Importantly, our data suggest that compound 12 and PZQ exert different antischistosomal activities. More studies will be necessary to confirm the generated hypothesis and to progress the development of more potent antischistosomal sclareol derivatives.

The repositioning of epigenetic probes/inhibitors identifies new anti-schistosomal lead compounds and chemotherapeutic targets

“…The current cornerstone of schistosomiasis control in endemic communities is preventative chemotherapy with praziquantel (PZQ), a pyrazinoisoquinoline-like compound that induces minimal side effects and demonstrates a highly-favourable absorption, distribution, metabolism and excretion (ADME) profile [4]. However, as PZQ has been the primary anti-schistosomal used across the globe for the past three decades [5] and its currently unknown mechanism of action (possibly modulating serotonin signalling; [6, 7]) is variably effective against intra-human schistosome lifecycle stages [8], the search for PZQ replacement or combinatorial drugs is under intense investigation should drug resistant schistosomes develop.…”

Specific Antibodies and Arachidonic Acid Mediate the Protection Induced by the Schistosoma mansoni Cysteine Peptidase-Based Vaccine in Mice

“…Intense immunologic reactions would force the liver-stage schistosomes to escape via extravasation to the hepatic tissue and certain death [49]. (5) ARA is a documented schistosomicide [34][35][36][37][38] and a putative endoschistosomicide [9,[39][40][41][42]. The significant (p < 0.05), yet limited, increase in serum ARA is not expected to directly kill juvenile worms.…”

Identification of 6-(piperazin-1-yl)-1,3,5-triazine as a chemical scaffold with broad anti-schistosomal activities

“…The parasites were then killed by incubation in a solution of 0.6 mM magnesium chloride (MgCl 2 ) for 1 min. Afterwards, adult schistosome worms were briefly washed with pre-warmed 1X PBS and then fixed using appropriate solutions for analysis by scanning electron microscopy (SEM) as previously described in literature 58 , 61 , 62 .…”