Anthelmintic evaluation of triterpenes derived from conifers (family Pinaceae) on the digenean parasite Fasciola hepatica

Fasciolosis is a devastating food borne parasitic disease of ruminants and is mainly caused by infection with the trematode Fasciola hepatica (liver fluke) in temperate climates. The primary strategy of fasciolosis control relies on a single drug, triclabendazole, although nitroxinil, albendazole, closantel, rafoxanide and clorsulon can also be used to treat chronic infections. Unfortunately, growing evidence indicates that triclabendazole resistant liver fluke populations are pervasive. Therefore, identifying new chemical matter with anthelmintic properties as starting points for drug development is urgently needed. Here, we continue our studies into the flukicidal activities of plant derived natural products isolated and purified from coniferous trees. Amongst nine triterpenes studied, Abies grandis derived 700235 represents a novel chemical entity with pronounced ex vivo paralytic activity that led to death in the majority of F. hepatica Newly Excysted Juveniles (NEJs) at 10 μM after 72 h. In adults, paralytic activity was also observed in some individuals at higher concentrations (13.3 and 40 μM). While the mechanism of action is currently unknown, the anthelmintic activity of 700235 (and related triterpenes) is linked to the presence of both a steroid-like tetracyclic nucleus and a side lactone ring. Although some epithelial cell cytotoxicity developed in time (CC₅₀s on Madin-Darby bovine kidney cells - 68.9 μM at 24 h and 16.7 μM at 72 h), 700235 is predicted to display many favorable ADMET, PK and drug-like characteristics suitable for further consideration as a starting point in the search for new flukicides to treat fasciolosis.