Assessing the anthelmintic activity of pyrazole-5-carboxamide derivatives against Haemonchus contortus.
Parasit Vectors. 2017 May 31;10(1):272
Authors: Jiao Y, Preston S, Song H, Jabbar A, Liu Y, Baell J, Hofmann A, Hutchinson D, Wang T, Koehler AV, Fisher GM, Andrews KT, Laleu B, Palmer MJ, Burrows JN, Wells TNC, Wang Q, Gasser RB
BACKGROUND: In this study, we tested five series of pyrazole-5-carboxamide compounds (n = 55) for activity against parasitic stages of the nematode Haemonchus contortus (barber's pole worm), one of the most pathogenic parasites of ruminants.
METHODS: In an optimised, whole-organism screening assay, using exsheathed third-stage (xL3) and fourth-stage (L4) larvae, we measured the inhibition of larval motility and development of H. contortus.
RESULTS: Amongst the 55 compounds, we identified two compounds (designated a-15 and a-17) that reproducibly inhibit xL3 motility as well as L4 motility and development, with IC50 values ranging between ~3.4 and 55.6 μM. We studied the effect of these two 'hit' compounds on mitochondrial function by measuring oxygen consumption. This assessment showed that xL3s exposed to each of these compounds consumed significantly less oxygen and had less mitochondrial activity than untreated xL3s, which was consistent with specific inhibition of complex I of the respiratory electron transport chain in arthropods.
CONCLUSIONS: The present findings provide a sound basis for future work, aimed at identifying the targets of compounds a-15 and a-17 and establishing the modes of action of these chemicals in H. contortus.
PMID: 28569174 [PubMed - indexed for MEDLINE]
How do the macrocyclic lactones kill filarial nematode larvae?
Invert Neurosci. 2016 09;16(3):7
Authors: Wolstenholme AJ, Maclean MJ, Coates R, McCoy CJ, Reaves BJ
The macrocyclic lactones (MLs) are one of the few classes of drug used in the control of the human filarial infections, onchocerciasis and lymphatic filariasis, and the only one used to prevent heartworm disease in dogs and cats. Despite their importance in preventing filarial diseases, the way in which the MLs work against these parasites is unclear. In vitro measurements of nematode motility have revealed a large discrepancy between the maximum plasma concentrations achieved after drug administration and the amounts required to paralyze worms. Recent evidence has shed new light on the likely functions of the ML target, glutamate-gated chloride channels, in filarial nematodes and supports the hypothesis that the rapid clearance of microfilariae that follows treatment involves the host immune system.
PMID: 27279086 [PubMed - indexed for MEDLINE]