- Title
- 1-Methyl-1 H-pyrazole-5-carboxamide derivatives exhibit unexpected acute mammalian toxicity
- Creator
- Preston, Sarah; Garcia-Bustos, Jose; Hall, Liam; Martin, Sheree; Le, Thuy
- Date
- 2021
- Type
- Text; Journal article
- Identifier
- http://researchonline.federation.edu.au/vital/access/HandleResolver/1959.17/175560
- Identifier
- vital:15021
- Identifier
-
https://doi.org/10.1021/acs.jmedchem.0c01793
- Identifier
- ISBN:0022-2623 (ISSN)
- Abstract
- A series of 1-methyl-1H-pyrazole-5-carboxamides were synthesized as potent inhibitors of the parasitic nematode of sheep, Haemonchus contortus. These compounds did not show overt cytotoxicity to a range of mammalian cell lines under standard in vitro culture conditions, had high selectivity indices, and were progressed to an acute toxicity study in a rodent model. Strikingly, acute toxicity was observed in mice. Experiments measuring cellular respiration showed a dose-dependent inhibition of mitochondrial respiration. Under these conditions, potent cytotoxicity was observed for these compounds in rat hepatocytes suggesting that the potent acute mammalian toxicity of this chemotype is most likely associated with respiratory inhibition. In contrast, parasite toxicity was not correlated to acute toxicity or cytotoxicity in respiring cells. This paper highlights the importance of identifying an appropriate in vitro predictor of in vivo toxicity early on in the drug discovery pipeline, in particular assessment for in vitro mitochondrial toxicity. © 2020 American Chemical Society. *Please note that there are multiple authors for this article therefore only the name of the first 5 including Federation University Australia affiliate “Sarah Preston” is provided in this record**
- Publisher
- American Chemical Society
- Relation
- Journal of Medicinal Chemistry Vol. 64, no. 1 (2021), p. 840-844
- Rights
- All metadata describing materials held in, or linked to, the repository is freely available under a CC0 licence
- Rights
- Copyright © 2020 American Chemical Society
- Subject
- 0304 Medicinal and Biomolecular Chemistry; 0305 Organic Chemistry; 1115 Pharmacology and Pharmaceutical Sciences
- Reviewed
- Funder
- This work was funded through grants from the Australian Research Council (ARC; R.B.G., J.B.B., and A.J.) and the National Health and Medical Research Council (NHMRC; R.B.G.) of Australia and Yourgene Bioscience Taiwan (R.B.G.). Fellowship support (J.B.) was from the National Health and Medical Research Council of Australia (NHMRC) (2012–2016 Senior Research Fellowship #1020411, 2017- Principal Research Fellowship #1117602). Also acknowledged is Australian Federal Government Education Investment Fund Super Science Initiative and the Victorian State Government, Victoria Science Agenda Investment Fund for infrastructure support, and the facilities, and the scientific and technical assistance of the Australian Translational Medicinal Chemistry Facility (ATMCF), Monash Institute of Pharmaceutical Sciences (MIPS). ATMCF is supported by Therapeutic Innovation Australia (TIA). TIA is supported by the Australian Government through the National Collaborative Research Infrastructure Strategy (NCRIS) program.
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