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Int J Parasitol Drugs Drug Resist. 2018 Apr;8(1):1-7. doi: 10.1016/j.ijpddr.2017.11.005. Epub 2017 Nov 29.

Polypyridylruthenium(II) complexes exert in vitro and in vivo nematocidal activity and show significant inhibition of parasite acetylcholinesterases.

Author information

1
School of Physical, Environmental and Mathematical Sciences, UNSW (ADFA), Canberra, Australian Capital Territory, 2612, Australia.
2
Centre for Biodiscovery and Molecular Development of Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, Queensland, 4878, Australia.
3
Centre for Biodiscovery and Molecular Development of Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, Queensland, 4878, Australia; School of Physical Sciences, University of Adelaide, Adelaide, South Australia, 5005, Australia.
4
Centre for Biodiscovery and Molecular Development of Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, Queensland, 4878, Australia. Electronic address: mark.pearson@jcu.edu.au.

Abstract

Over 4.5 billion people are at risk of infection with soil transmitted helminths and there are concerns about the development of resistance to the handful of frontline nematocides in endemic populations. We investigated the anti-nematode efficacy of a series of polypyridylruthenium(II) complexes and showed they were active against L3 and adult stages of Trichuris muris, the rodent homologue of the causative agent of human trichuriasis, T. trichiura. One of the compounds, Rubb12-mono, which was among the most potent in its ability to kill L3 (IC50 = 3.1 ± 0.4 μM) and adult (IC50 = 5.2 ± 0.3 μM) stage worms was assessed for efficacy in a mouse model of trichuriasis by administering 3 consecutive daily oral doses of the drug 3 weeks post infection with the murine whipworm Trichuris muris. Mice treated with Rubb12-mono showed an average 66% reduction (P = 0.015) in faecal egg count over two independent trials. The drugs partially exerted their activity through inhibition of acetylcholinesterases, as worms treated in vitro and in vivo showed significant decreases in the activity of this class of enzymes. Our data show that ruthenium complexes are effective against T. muris, a model gastro-intestinal nematode and soil-transmitted helminth. Further, knowledge of the target of ruthenium drugs can facilitate modification of current compounds to identify analogues which are even more effective and selective against Trichuris and other helminths of human and veterinary importance.

KEYWORDS:

Acetylcholinesterase; Anthelmintic; Ruthenium complex; Trichuris muris

PMID:
29207309
PMCID:
PMC5724747
DOI:
10.1016/j.ijpddr.2017.11.005
[Indexed for MEDLINE]
Free PMC Article

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