Exploration of 3-methylisoquinoline-4-carbonitriles as protein kinase A inhibitors of Plasmodium falciparum.
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.
Department of Chemistry and Physics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria 3086, Australia.
Melissa J
MJ
Buskes
Centre for Biomedical Research, Burnet Institute, Melbourne, Victoria 3004, Australia.
Katherine L
KL
Harvey
Centre for Biomedical Research, Burnet Institute, Melbourne, Victoria 3004, Australia.
Boris
B
Prinz
Centre for Biomedical Research, Burnet Institute, Melbourne, Victoria 3004, Australia; Monash University, Melbourne, Victoria 3800, Australia; University of Melbourne, Melbourne 3010, Australia.
Brendan S
BS
Crabb
Centre for Biomedical Research, Burnet Institute, Melbourne, Victoria 3004, Australia; Monash University, Melbourne, Victoria 3800, Australia.
Paul R
PR
Gilson
Department of Chemistry and Physics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria 3086, Australia.
David J D
DJD
Wilson
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.
Belinda M
BM
Abbott
D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D007546:Isoquinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D009570:Nitriles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D007546:Isoquinolines; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D017868:Cyclic AMP-Dependent Protein Kinases
Antimalarials; Inhibitors; Isoquinolines; Protein Kinase A