Journal article

Structure-Activity Relationship Studies of Tolfenpyrad Reveal Subnanomolar Inhibitors of Haemonchus contortus Development

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



Recently, we have discovered that the registered pesticide, tolfenpyrad, unexpectedly and potently inhibits the development of the L4 larval stage of the parasitic nematode Haemonchus contortus with an IC50 value of 0.03 μM while displaying good selectivity, with an IC50 of 37.9 μM for cytotoxicity. As a promising molecular template for medicinal chemistry optimization, we undertook anthelmintic structure-activity relationships for this chemical. Modifications of the left-hand side (LHS), right-hand side (RHS), and middle section of the scaffold were explored to produce a set of 57 analogues. Analogues 25, 29, and 33 were shown to be the most potent compounds of the series, with IC50 values ..

View full abstract


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 #1020411, 2017- Principal Research Fellowship #1117602). Also acknowledged are 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 was supported by Therapeutic Innovation Australia (TIA). TIA was 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.