Abstract
Two economically and biomedically important platyhelminth species, Fasciola hepatica (liver fluke) and Schistosoma mansoni (blood fluke), are responsible for the neglected tropical diseases (NTDs) fasciolosis and schistosomiasis. Due to the absence of prophylactic vaccines, these NTDs are principally managed by the single class chemotherapies triclabendazole (F. hepatica) and praziquantel (S. mansoni). Unfortunately, liver fluke resistance to triclabendazole has been widely reported and blood fluke insensitivity/resistance to praziquantel has been observed in both laboratory settings as well as in endemic communities. Therefore, the identification of new anthelmintics is necessary for the sustainable control of these NTDs in both animal and human populations. Here, continuing our work with phytochemicals, we isolated ten triterpenoids from the mature bark of Abies species and assessed their anthelmintic activities against F. hepatica and S. mansoni larval and adult lifecycle stages. Full 1H and 13C NMR-mediated structural elucidation of the two most active triterpenoids revealed that a tetracyclic steroid-like nucleus core and a lactone side chain are associated with the observed anthelmintic effects. When compared to representative mammalian cell lines (MDBK and HepG2), the most potent triterpenoid (700015; anthelmintic EC50s range from 0.7 μM–15.6 μM) displayed anthelmintic selectivity (selectivity indices for F. hepatica: 13 for newly excysted juveniles, 46 for immature flukes, 2 for mature flukes; selectivity indices for S. mansoni: 14 for schistosomula, 9 for immature flukes, 4 for adult males and 3 for adult females) and induced severe disruption of surface membranes in both liver and blood flukes. S. mansoni egg production, a process responsible for pathology in schistosomiasis, was also severely inhibited by 700015. Together, our results describe the structural elucidation of a novel broad acting anthelmintic triterpenoid and support further investigations developing this compound into more potent analogues for the control of both fasciolosis and schistosomiasis.
Highlights
The Neglected Tropical Disease (NTD) causing flatworms Fasciola hepatica and Schistosoma mansoni are amongst some of the most successful parasites on the planet (Collins, 2017)
Full 1H and 13C Nuclear Magnetic Resonance (NMR)-mediated structural elucidation of the two most active triterpenoids revealed that a tetracyclic steroid-like nucleus core and a lactone side chain are associated with the observed anthelmintic effects
Investment in drug discovery research for NTDs is disproportionately low when compared to the impact that these diseases have on both animal and human lives
Summary
The Neglected Tropical Disease (NTD) causing flatworms Fasciola hepatica (liver fluke responsible for fasciolosis) and Schistosoma mansoni (blood fluke responsible for schistosomiasis) are amongst some of the most successful parasites on the planet (Collins, 2017). The long-term consequences of chronic inflammation leads to disease development in more than 200 million people per annum, often killing thousands to hundreds of thousands in endemic areas every year (Hotez and Fenwick, 2009) When considering that both fasciolosis and schistosomiasis are often found coendemic (Esteban et al, 2003; Yabe et al, 2008; Krauth et al, 2015), tremendous pressure in the health care budgets and One-Health objectives can develop in countries where resources are insufficient to meet competing financial demands. A single compound that displays dual activity against definitive host lifecycle stages (juveniles, immature and mature flukes) of both liver and blood flukes would be advantageous in contributing to the control of fasciolosis and schistosomiasis Towards this end, we previously have described the anthelmintic effects of a Lycium chinense derived diterpenoid, 7-keto-sempervirol, against both F. hepatica and S. mansoni juveniles and adults (Edwards et al, 2015). These results extend the chemical space of plantbased natural products, which display anthelmintic activity against flukes of both veterinary and biomedical importance
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