title: Compounds Derived from the Bhutanese Daisy, Ajania nubigena, Demonstrate Dual Anthelmintic Activity against Schistosoma mansoni and Trichuris muris.
abstract: Whipworms and blood flukes combined infect almost one billion people in developing countries. Only a handful of anthelmintic drugs are currently available to treat these infections effectively; there is therefore an urgent need for new generations of anthelmintic compounds. Medicinal plants have presented as a viable source of new parasiticides. Ajania nubigena, the Bhutanese daisy, has been used in Bhutanese traditional medicine for treating various diseases and our previous studies revealed that small molecules from this plant have antimalarial properties. Encouraged by these findings, we screened four major compounds isolated from A. nubigena for their anthelmintic properties.
  
  
  
  Here we studied four major compounds derived from A. nubigena for their anthelmintic properties against the nematode whipworm Trichuris muris and the platyhelminth blood fluke Schistosoma mansoni using the xWORM assay technique. Of four compounds tested, two compounds-luteolin (3) and (3R,6R)-linalool oxide acetate (1)-showed dual anthelmintic activity against S. mansoni (IC50 range = 5.8-36.9 μg/mL) and T. muris (IC50 range = 9.7-20.4 μg/mL). Using scanning electron microscopy, we determined luteolin as the most efficacious compound against both parasites and additionally was found effective against the schistosomula, the infective stage of S. mansoni (IC50 = 13.3 μg/mL). Luteolin induced tegumental damage to S. mansoni and affected the cuticle, bacillary bands and bacillary glands of T. muris. Our in vivo assessment of luteolin (3) against T. muris infection at a single oral dosing of 100 mg/kg, despite being significantly (27.6%) better than the untreated control group, was markedly weaker than mebendazole (93.1%) in reducing the worm burden in mice.
  
  
  
  Among the four compounds tested, luteolin demonstrated the best broad-spectrum activity against two different helminths-T. muris and S. mansoni-and was effective against juvenile schistosomes, the stage that is refractory to the current gold standard drug, praziquantel. Medicinal chemistry optimisation including cytotoxicity analysis, analogue development and structure-activity relationship studies are warranted and could lead to the identification of more potent chemical entities for the control of parasitic helminths of humans and animals.
authors.affiliation: Centre for Biodiscovery and Molecular Development of Therapeutics, Queensland Tropical Health Alliance, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns Campus, Cairns, Australia.
authors.forename: Phurpa
authors.identifier: 0000-0002-4381-7382
authors.initials: P
authors.lastname: Wangchuk
authors.affiliation: Centre for Biodiscovery and Molecular Development of Therapeutics, Queensland Tropical Health Alliance, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns Campus, Cairns, Australia.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Pearson
authors.affiliation: Centre for Biodiscovery and Molecular Development of Therapeutics, Queensland Tropical Health Alliance, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns Campus, Cairns, Australia.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Giacomin
authors.affiliation: Centre for Biodiscovery and Molecular Development of Therapeutics, Queensland Tropical Health Alliance, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns Campus, Cairns, Australia.
authors.forename: Luke
authors.initials: L
authors.lastname: Becker
authors.affiliation: Centre for Biodiscovery and Molecular Development of Therapeutics, Queensland Tropical Health Alliance, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns Campus, Cairns, Australia.
authors.forename: Javier
authors.initials: J
authors.lastname: Sotillo
authors.affiliation: Centre for Biodiscovery and Molecular Development of Therapeutics, Queensland Tropical Health Alliance, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns Campus, Cairns, Australia.
authors.forename: Darren
authors.initials: D
authors.lastname: Pickering
authors.affiliation: Centre for Biodiscovery and Molecular Development of Therapeutics, Queensland Tropical Health Alliance, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns Campus, Cairns, Australia.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Smout
authors.affiliation: Centre for Biodiscovery and Molecular Development of Therapeutics, Queensland Tropical Health Alliance, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns Campus, Cairns, Australia.
authors.forename: Alex
authors.initials: A
authors.lastname: Loukas
mesh_terms: D000818:Animals; D000871:Anthelmintics / Q000494:pharmacology*; D019659:Asteraceae / Q000737:chemistry; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008855:Microscopy, Electron, Scanning; D010936:Plant Extracts / Q000494:pharmacology*; D010946:Plants, Medicinal / Q000737:chemistry; D011223:Praziquantel / Q000494:pharmacology; D012550:Schistosoma mansoni / Q000187:drug effects*; D012555:Schistosomiasis mansoni / Q000188:drug therapy*; D013329:Structure-Activity Relationship; D014257:Trichuriasis / Q000188:drug therapy*; D014258:Trichuris / Q000187:drug effects*
chemical_list: D000871:Anthelmintics; D010936:Plant Extracts; D011223:Praziquantel