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1-Methyl-1H-pyrazole-5-carboxamide Derivatives Exhibit Unexpected Acute Mammalian Toxicity. 2021
Sarah Preston, and
Jose Garcia-Bustos, and
Liam G Hall, and
Sheree D Martin, and
Thuy G Le, and
Abhijit Kundu, and
Atanu Ghoshal, and
Nghi H Nguyen, and
Yaqing Jiao, and
Banfeng Ruan, and
Lian Xue, and
Fei Huang, and
Bill C H Chang, and
Sean L McGee, and
Timothy N C Wells, and
Michael J Palmer, and
Abdul Jabbar, and
Robin B Gasser, and
Jonathan B Baell
School of Health and Life Sciences, Federation University, Ballarat, Victoria 3353, Australia.
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.
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