Journal article

Novel 1-Methyl-1H-pyrazole-5-carboxamide Derivatives with Potent Anthelmintic Activity

Thuy G Le, Abhijit Kundu, Atanu Ghoshal, Nghi H Nguyen, Sarah Preston, Yaqing Jiao, Banfeng Ruan, Lian Xue, Fei Huang, Jennifer Keiser, Andreas Hofmann, Bill CH Chang, Jose Garcia-Bustos, Timothy NC Wells, Michael J Palmer, Abdul Jabbar, Robin B Gasser, Jonathan B Baell

Journal of Medicinal Chemistry | American Chemical Society | Published : 2019


A phenotypic screen of two different libraries of small molecules against the motility and development of the parasitic nematode Haemonchus contortus led to the identification of two 1-methyl-1H-pyrazole-5-carboxamide derivatives. Medicinal chemistry optimization targeted modifications of the left-hand side, middle section, and right-hand side of the hybrid structure of these two hits to elucidate the structure–activity relationship (SAR). Initial SAR around these hits allowed for the iterative and directed assembly of a focused set of 30 analogues of their hybrid structure. Compounds 10, 17, 20, and 22 were identified as the most potent compounds, inhibiting the development of the fourth la..

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Awarded by National Health and Medical Research Council of Australia (NHMRC)

Funding Acknowledgements

Support from the Australian Research Council (ARC), the Medicines for Malaria Venture (MMV), and the Yourgene Bioscience is gratefully acknowledged. Fellowship support (J.B.B.) was from the National Health and Medical Research Council of Australia (NHMRC) (2012-2016 Senior Research Fellowship #1020411, 2017-Principal Research Fellowship #1117602). The authors acknowledge the infrastructure support and facilities provided by the Australian Federal Government Education Investment Fund Super Science Initiative and the Victorian State Government, Victoria Science Agenda Investment Fund. The authors also acknowledge the scientific and technical assistance of the Australian Translational Medicinal Chemistry Facility (ATMCF), Monash Institute of Pharmaceutical Sciences (MIPS). ATMCF is supported by the Therapeutic Innovation Australia (TIA). TIA is supported by the Australian Government through the National Collaborative Research Infrastructure Strategy (NCRIS) program. The Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, is acknowledged for their conduct of the ADME screening studies. We thank our colleagues at Medicines for Malaria Venture (MMV) for their support. We also thank A/Prof Kaylene J. Simpson and Karla J. Cowley, Victorian Centre for Functional Genomics, Peter MacCallum Cancer Centre, Parkville, Victoria, for cytotoxicity testing; this Centre is supported by funding from the Australian Government's Education Investment Fund through the Super Science Initiative and the Peter MacCallum Cancer Centre Foundation (KJS). We thank anonymous reviewers for the constructive comments and suggestions on our manuscript.