Journal article
Exploration of 3-methylisoquinoline-4-carbonitriles as protein kinase A inhibitors of Plasmodium falciparum
MJ Buskes, KL Harvey, B Prinz, BS Crabb, PR Gilson, DJD Wilson, BM Abbott
Bioorganic and Medicinal Chemistry | PERGAMON-ELSEVIER SCIENCE LTD | Published : 2016
Abstract
A series of isoquinolines have been evaluated in a homology model of Plasmodium falciparum Protein Kinase A (PfPKA) using molecular dynamics. Synthesis of these compounds was then undertaken to investigate their structure-activity relationships. One compound was found to inhibit parasite growth in an in vitro assay and provides a lead to further develop 3-methylisoquinoline-4-carbonitriles as antimalarial compounds. Development of a potent and selective PfPKA inhibitor would provide a useful tool to shed further insight into the mechanisms enabling malaria parasites to establish infection.
Grants
Funding Acknowledgements
M.B. acknowledges the support of the CRC for Biomarker Translation, funded by the Australian Government, in the provision of her postgraduate scholarship. K.H. is the recipient of an Australian Postgraduate Award from the University of Melbourne, Australia. The authors thank Dr. Leslie W. Deady for helpful discussions (Department of Chemistry and Physics, La Trobe Institute for Molecular Science, La Trobe University), and Dr. Jason Dang (Monash Institute of Pharmaceutical Sciences, Monash University) for HRMS analysis. The authors acknowledge support from the Victorian Partnership for Advanced Computing (VPAC) and the Victorian Life Science Computing Initiative (VLSCI). This work was supported by grants from the National Health and Medical Research Council (NHMRC) of Australia. The authors gratefully acknowledge the contribution of the Victorian Operational Infrastructure Support Program, Australia received by the Burnet Institute.