2. Academic Validation
  3. 1-Methyl-1 H-pyrazole-5-carboxamide Derivatives Exhibit Unexpected Acute Mammalian Toxicity

1-Methyl-1 H-pyrazole-5-carboxamide Derivatives Exhibit Unexpected Acute Mammalian Toxicity

  • J Med Chem. 2021 Jan 14;64(1):840-844. doi: 10.1021/acs.jmedchem.0c01793.
Sarah Preston 1,  Jose Garcia-Bustos 2,  Liam G Hall 3,  Sheree D Martin 3,  Thuy G Le 4,  Abhijit Kundu 5,  Atanu Ghoshal 5,  Nghi H Nguyen 4,  Yaqing Jiao 2,  Banfeng Ruan 4,  Lian Xue 4,  Fei Huang 6,  Bill C H Chang 7,  Sean L McGee 3,  Timothy N C Wells 8,  Michael J Palmer 8,  Abdul Jabbar 2,  Robin B Gasser 2,  Jonathan B Baell 6 4
Affiliations

Affiliations

  • 1 School of Health and Life Sciences, Federation University, Ballarat, Victoria 3353, Australia.
  • 2 Department of Veterinary Biosciences, Melbourne Veterinary School, Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, Victoria 3010, Australia.
  • 3 Metabolic Research Unit, Metabolic Reprogramming Laboratory, School of Medicine, Faculty of Health, Deakin University, Waurn Ponds, Victoria 3216, Australia.
  • 4 Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
  • 5 TCG Lifesciences Private Limited, Block BN, Plot 7, Salt-lake Electronics Complex, Sector V, Kolkata 700091, West Bengal, India.
  • 6 School of Pharmaceutical Sciences, Nanjing Tech University, No. 30 South Puzhu Road, Nanjing 211816, People's Republic of China.
  • 7 Yourgene, Bioscience, Taipei 23863, Taiwan.
  • 8 Medicines for Malaria Venture, 1215 Geneva, Switzerland.
PMID: 33352050 DOI: 10.1021/acs.jmedchem.0c01793
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.

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