Selenophene and thiophene-core estrogen receptor ligands that inhibit motility and development of parasitic stages of Haemonchus contortus.
Parasitic worms represent a substantial disease burden in animals and humans worldwide. The control of parasitic roundworms (nematodes) relies heavily on the use of anthelmintic drugs. However, widespread drug resistance in nematodes seriously compromises the effectiveness of many anthelmintics around the world. Thus, there is a need to discover new drugs, with unique modes of action, against parasites.



Here, we synthesised and tested 74 selective estrogen receptor modulators (SERMs) for in vitro-activity on parasitic larvae of Haemonchus contortus (barber's pole worm), one of the most important nematode pathogens of small ruminants (including sheep and goats) and a key representative of one of the largest groups of parasitic nematodes (the Strongylida) of animals. We also studied the morphology of treated and untreated larvae using scanning electron microscopy (SEM), and assessed the agonistic/antagonistic activity of SERMs in a human embryonic kidney cell line using a luciferase reporter assay system.



We identified three SERMs (one selenophene and two thiophene-core compounds) with potent inhibitory activities (at 3-25 μM) on the motility and development of parasitic stages of H. contortus. An SEM examination of treated H. contortus revealed considerable damage to the cuticle of fourth- but not exsheathed, third-stage larvae; this damage appeared to be consistent with that observed upon treatment with monepantel but not moxidectin (control compounds).



The potency of the three SERMs compared favourably with commercially available anthelmintics, such that they warrant further assessment as nematocides. Future studies could focus on assessing the selectivity of these SERMs to parasites, characterising their target(s) and/or designing analogs that are parasite-specific.
Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, VIC, 3010, Australia.
Sarah
S
Preston
Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Wuhan University School of Pharmaceutical Sciences, Wuhan, 430072, China.
Junjie
J
Luo
Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, VIC, 3010, Australia.|Medicinal Chemistry, Monash University Institute of Pharmaceutical Sciences (MIPS), Monash University, Parkville, VIC, 3052, Australia.|State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei, 430070, China.
Yuezhou
Y
Zhang
Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, VIC, 3010, Australia.
Abdul
A
Jabbar
School of Biosciences, The University of Melbourne, Parkville, VIC, 3010, Australia.
Simon
S
Crawford
Medicinal Chemistry, Monash University Institute of Pharmaceutical Sciences (MIPS), Monash University, Parkville, VIC, 3052, Australia.
Jonathan
J
Baell
Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, VIC, 3010, Australia.|Structural Chemistry Program, Eskitis Institute for Drug Discovery, Griffith University, Brisbane, QLD, 4111, Australia.
Andreas
A
Hofmann
State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei, 430070, China.
Min
M
Hu
Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Wuhan University School of Pharmaceutical Sciences, Wuhan, 430072, China. zhouhb@whu.edu.cn.
Hai-Bing
HB
Zhou
Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, VIC, 3010, Australia. robinbg@unimelb.edu.au.|Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Wuhan University School of Pharmaceutical Sciences, Wuhan, 430072, China. robinbg@unimelb.edu.au.
Robin B
RB
Gasser
D000607:Aminoacetonitrile / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000977:Antiparasitic Agents / Q000737:chemistry / Q000494:pharmacology*; D006189:Haemonchus / Q000187:drug effects* / Q000254:growth & development; D018942:Macrolides / Q000494:pharmacology; D015394:Molecular Structure; D016566:Organoselenium Compounds / Q000737:chemistry / Q000494:pharmacology*; D010636:Phenols / Q000737:chemistry / Q000494:pharmacology*; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013457:Sulfur Compounds / Q000737:chemistry / Q000494:pharmacology*; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology*
D000977:Antiparasitic Agents; C000614434:MJ-17 compound; C000614435:MJ-22 compound; D018942:Macrolides; D016566:Organoselenium Compounds; D010636:Phenols; D011960:Receptors, Estrogen; D013457:Sulfur Compounds; D013876:Thiophenes; C000614433:WZY-2 compound; D000607:Aminoacetonitrile; C533978:monepantel; C027837:moxidectin
Haemonchus contortus; Inhibitory activity; Nematode; Selective estrogen receptor modulators (SERMs); Selenophene and thiophene-core SERMs