1. An Abies procera-derived tetracyclic triterpene containing a steroid-like nucleus core and a lactone side chain attenuates in vitro survival of both Fasciola hepatica and Schistosoma mansoni.
- Author
-
Whiteland HL, Chakroborty A, Forde-Thomas JE, Crusco A, Cookson A, Hollinshead J, Fenn CA, Bartholomew B, Holdsworth PA, Fisher M, Nash RJ, and Hoffmann KF
- Subjects
- Abies anatomy & histology, Animals, Anthelmintics chemistry, Fasciola hepatica physiology, Fascioliasis drug therapy, Fascioliasis parasitology, Female, Hep G2 Cells, Humans, Lactones chemistry, Life Cycle Stages drug effects, Male, Neglected Diseases drug therapy, Phytochemicals chemistry, Phytochemicals isolation & purification, Phytochemicals pharmacology, Plant Bark chemistry, Schistosoma mansoni physiology, Schistosomiasis drug therapy, Schistosomiasis parasitology, Triterpenes chemistry, Triterpenes isolation & purification, Abies chemistry, Anthelmintics pharmacology, Drug Discovery, Fasciola hepatica drug effects, Lactones pharmacology, Schistosoma mansoni drug effects, Triterpenes pharmacology
- 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
1 H and13 C 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 EC50 s 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., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)- Published
- 2018
- Full Text
- View/download PDF