Selenophene and thiophene-core estrogen receptor ligands that inhibit motility and development of parasitic stages of Haemonchus contortus

Abstract

BackgroundParasitic 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.MethodsHere, 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.ResultsWe 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).ConclusionThe 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13071-016-1612-4) contains supplementary material, which is available to authorized users.

Screening of the ‘Open Scaffolds’ collection from Compounds Australia identifies a new chemical entity with anthelmintic activities against different developmental stages of the barber's pole worm and other parasitic nematodes

“…This difference in potency might be due to variation in expression of its target(s) in the nematode, a distinction in physiology between these two developmental stages of the worm and/or the nature and extent of the uptake of the compound by the worm. An integrated use of transcriptomic, proteomic and metabolomic techniques ( Mikami et al., 2012 , Schwarz et al., 2013 , Preston et al., 2016c ) might be able to elucidate the physiological and biological pathways in H. contortus and/or other worms affected by SN00797439.…”

Deguelin exerts potent nematocidal activity via the mitochondrial respiratory chain

“…Scanning electron microscopy (SEM) was used to assess whether deguelin causes structural damage to the larval stages of H. contortus, as previously described (43). In brief, deguelin and positive control compounds-monepantel and moxidectinwere each diluted to a final concentration of 100 mM in LB* and incubated with exsheathed L3s or L4s in wells of a 96-well plate at a density of 6000 larvae/ml for 24 h at 38°C and 10% CO 2 .…”

Selenophenes: Introducing a New Element into the Core of Non‐Steroidal Estrogen Receptor Ligands

“…In addition, a number of biologically active selenaheterocycles, such as cytoprotective agent ebselen, have recently been discovered . Moreover, we and other found that a few selenophene compounds inhibited the motility and development of stages of the comparable nematode Haemonchus contortus . More recently, fluselenamyl, a novel planar benzoselenazole derivative, was used as a PET imaging agent for amyloid in Alzheimer's disease (Figure )…”