Journal article

Optimization of Novel 1-Methyl-1H-Pyrazole-5-carboxamides Leads to High Potency Larval Development Inhibitors of the Barber's Pole Worm

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, Abdul Jabbar, Timothy NC Wells, Michael J Palmer, Robin B Gasser, Jonathan B Baell



A phenotypic screen of a diverse library of small molecules for inhibition of the development of larvae of the parasitic nematode Haemonchus contortus led to the identification of a 1-methyl-1 H-pyrazole-5-carboxamide derivative with an IC50 of 0.29 μM. Medicinal chemistry optimization targeted modifications on the left-hand side (LHS), middle section, and right-hand side (RHS) of the scaffold in order to elucidate the structure-activity relationship (SAR). Strong SAR allowed for the iterative and directed assembly of a focus set of 64 analogues, from which compound 60 was identified as the most potent compound, inhibiting the development of the fourth larval (L4) stage with an IC50 of 0.01 ..

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

Funding Acknowledgements

Support from the Australian Research Council (ARC), Medicines for Malaria Venture (MMV), and Yourgene Bioscience is gratefully acknowledged. Fellowship support (J.B.) was from the National Health and Medical Research Council of Australia (NHMRC) (2012-2016 Senior Research Fellowship no. 1020411, Principle Research Fellowship no. 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. The Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, is acknowledged for their conduct of the ADME screening studies. The Peter McCallum Cancer Centre is acknowledged for their conduct of the cytotoxicity studies.