1-Methyl-1H-pyrazole-5-carboxamide Derivatives Exhibit Unexpected Acute Mammalian Toxicity
Sarah Preston, Jose Garcia-Bustos, Liam G Hall, Sheree D Martin, Thuy G Le, Abhijit Kundu, Atanu Ghoshal, Nghi H Nguyen, Yaqing Jiao, Banfeng Ruan, Lian Xue, Fei Huang, Bill CH Chang, Sean L McGee, Timothy NC Wells, Michael J Palmer, Abdul Jabbar, Robin B Gasser, Jonathan B Baell
JOURNAL OF MEDICINAL CHEMISTRY | AMER CHEMICAL SOC | Published : 2021
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 li..View full abstract
Awarded by National Health and Medical Research Council of Australia (NHMRC)
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.