Selenophene and thiophene-core estrogen receptor ligands that inhibit motility and development of parasitic stages of Haemonchus contortus. Issue 1 (December 2016)

• Record Type: Journal Article
• Authors: Preston, Sarah; Luo, Junjie; Zhang, Yuezhou; Jabbar, Abdul; Crawford, Simon; Baell, Jonathan; Hofmann, Andreas; Hu, Min; Zhou, Hai-Bing; Gasser, Robin
• Is Part Of: Parasites & vectors. Volume 9:Issue 1(2016)
• Page Start: 1
• Page End: 11
• Publication Date: 2016-12
• Subjects: Selective estrogen receptor modulators (SERMs) -- Selenophene and thiophene-core SERMs -- Inhibitory activity -- Haemonchus contortus -- Nematode; Parasitism -- Periodicals; Parasites -- Periodicals; Vector-pathogen relationships -- Periodicals; Animals as carriers of disease -- Periodicals; Insects as carriers of disease -- Periodicals; 616.96
• DOI: 10.1186/s13071-016-1612-4
• Languages: English
• ISSNs: 1756-3305

Abstract

Abstract Background 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. Methods Here, we synthesised and tested 74 selective estrogen receptor modulators (SERMs) for in vitro- activity on parasitic larvae ofHaemonchus 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. Results 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 ofH. contortus . An SEM examination of treatedH. 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). Conclusion 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.