Anti-schistosomal properties of Sclareol and its Heck-coupled derivatives: design, synthesis, biological evaluation and untargeted metabolomics
ACS infectious diseases | 16 May 2019
A Crusco, H Whiteland, R Baptista, JE Forde-Thomas, M Beckmann, LAJ Mur, RJ Nash, AD Westwell and KF Hoffmann
Sclareol, a plant-derived diterpenoid widely used as a fragrance and flavouring 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, 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 sub-lethal 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 previously reported action of PZQ on serotonin signalling and/or effects on glycolysis. Importantly, our data suggest that compound 12 and PZQ exert different anti-schistosomal activities. More studies will be necessary to confirm the generated hypothesis and to progress the development of more potent anti-schistosomal sclareol derivatives.
* Data courtesy of Altmetric.com