Exploration of 3-methylisoquinoline-4-carbonitriles as protein kinase A inhibitors of Plasmodium falciparum

Melissa J Buskes; Katherine L Harvey; Boris Prinz; Brendan S Crabb; Paul R Gilson; David J D Wilson; Belinda M Abbott

doi:10.1016/j.bmc.2016.03.048

Exploration of 3-methylisoquinoline-4-carbonitriles as protein kinase A inhibitors of Plasmodium falciparum

Bioorg Med Chem. 2016 Jun 1;24(11):2389-2396. doi: 10.1016/j.bmc.2016.03.048. Epub 2016 Mar 28.

Authors

Melissa J Buskes¹, Katherine L Harvey², Boris Prinz², Brendan S Crabb³, Paul R Gilson⁴, David J D Wilson¹, Belinda M Abbott⁵

Affiliations

¹ Department of Chemistry and Physics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria 3086, Australia.
² Centre for Biomedical Research, Burnet Institute, Melbourne, Victoria 3004, Australia.
³ Centre for Biomedical Research, Burnet Institute, Melbourne, Victoria 3004, Australia; Monash University, Melbourne, Victoria 3800, Australia; University of Melbourne, Melbourne 3010, Australia.
⁴ Centre for Biomedical Research, Burnet Institute, Melbourne, Victoria 3004, Australia; Monash University, Melbourne, Victoria 3800, Australia.
⁵ Department of Chemistry and Physics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria 3086, Australia. Electronic address: b.abbott@latrobe.edu.au.

PMID: 27112453
DOI: 10.1016/j.bmc.2016.03.048

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.

Keywords: Antimalarials; Inhibitors; Isoquinolines; Protein Kinase A.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors*
Cyclic AMP-Dependent Protein Kinases / metabolism
Dose-Response Relationship, Drug
Isoquinolines / chemical synthesis
Isoquinolines / chemistry
Isoquinolines / pharmacology*
Molecular Structure
Nitriles / chemical synthesis
Nitriles / chemistry
Nitriles / pharmacology*
Parasitic Sensitivity Tests
Plasmodium falciparum / drug effects*
Plasmodium falciparum / enzymology
Plasmodium falciparum / growth & development
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Structure-Activity Relationship

Substances

Isoquinolines
Nitriles
Protein Kinase Inhibitors
Cyclic AMP-Dependent Protein Kinases