Identification of Fromiamycalin and Halaminol A from Australian Marine Sponge Extracts with Anthelmintic Activity against <em>Haemonchus contortus</em>
H. M. P. Dilrukshi Herath,
Sarah Preston,
Abdul Jabbar,
Jose Garcia-Bustos,
Aya C. Taki,
Russell S. Addison,
Sasha Hayes,
Karren D. Beattie,
Sean L. McGee,
Sheree D. Martin,
Merrick G. Ekins,
John N. A. Hooper,
Bill C. H. Chang,
Andreas Hofmann,
Rohan A. Davis,
Robin B. Gasser
Affiliations
H. M. P. Dilrukshi Herath
Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, Victoria 3010, Australia
Sarah Preston
Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, Victoria 3010, Australia
Abdul Jabbar
Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, Victoria 3010, Australia
Jose Garcia-Bustos
Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, Victoria 3010, Australia
Aya C. Taki
Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, Victoria 3010, Australia
Russell S. Addison
Griffith Institute for Drug Discovery, Griffith University, Brisbane, QLD 4111, Australia
Sasha Hayes
Griffith Institute for Drug Discovery, Griffith University, Brisbane, QLD 4111, Australia
Karren D. Beattie
Griffith Institute for Drug Discovery, Griffith University, Brisbane, QLD 4111, Australia
Sean L. McGee
Metabolic Research Unit, Metabolic Reprogramming Laboratory, School of Medicine, Faculty of Health, Deakin University, Waurn Ponds, Victoria 3216, Australia
Sheree D. Martin
Metabolic Research Unit, Metabolic Reprogramming Laboratory, School of Medicine, Faculty of Health, Deakin University, Waurn Ponds, Victoria 3216, Australia
Merrick G. Ekins
Queensland Museum, South Brisbane BC, QLD 4101, Australia
John N. A. Hooper
Queensland Museum, South Brisbane BC, QLD 4101, Australia
Bill C. H. Chang
Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, Victoria 3010, Australia
Andreas Hofmann
Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, Victoria 3010, Australia
Rohan A. Davis
Griffith Institute for Drug Discovery, Griffith University, Brisbane, QLD 4111, Australia
Robin B. Gasser
Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, Victoria 3010, Australia
There is an urgent need to discover and develop new anthelmintics for the treatment of parasitic nematodes of veterinary importance to circumvent challenges linked to drug resistant parasites. Being one of the most diverse natural ecosystems, the marine environment represents a rich resource of novel chemical entities. This study investigated 2000 extracts from marine invertebrates, collected from Australian waters, for anthelmintic activity. Using a well-established in vitro bioassay, these extracts were screened for nematocidal activity against Haemonchus contortus — a socioeconomically important parasitic nematode of livestock animals. Extracts (designated Mu-1, Ha-1 and Ha-2) from two marine sponges (Monanchora unguiculata and Haliclona sp.) each significantly affected larvae of H. contortus. Individual extracts displayed a dose-dependent inhibition of both the motility of exsheathed third-stage larvae (xL3s) and the development of xL3s to fourth-stage larvae (L4s). Active fractions in each of the three extracts were identified using bioassay-guided fractionation. From the active fractions from Monanchora unguiculata, a known pentacyclic guanidine alkaloid, fromiamycalin (1), was purified. This alkaloid was shown to be a moderately potent inhibitor of L4 development (half-maximum inhibitory concentration (IC50) = 26.6 ± 0.74 µM) and L4 motility (IC50 = 39.4 ± 4.83 µM), although it had a relatively low potency at inhibiting of xL3 motility (IC50 ≥ 100 µM). Investigation of the active fractions from the two Haliclona collections led to identification of a mixture of amino alcohol lipids, and, subsequently, a known natural product halaminol A (5). Anthelmintic profiling showed that 5 had limited potency at inhibiting larval development and motility. These data indicate that fromiamycalin, other related pentacyclic guanidine alkaloids and/or halaminols could have potential as anthelmintics following future medicinal chemistry efforts.
