Antimalarial activity of novel 4-cyano-3-methylisoquinoline inhibitors against Plasmodium falciparum: design, synthesis and biological evaluation.
Central to malaria pathogenesis is the invasion of human red blood cells by Plasmodium falciparum parasites. Following each cycle of intracellular development and replication, parasites activate a cellular program to egress from their current host cell and invade a new one. The orchestration of this process critically relies upon numerous organised phospho-signaling cascades, which are mediated by a number of central kinases. Parasite kinases are emerging as novel antimalarial targets as they have diverged sufficiently from their mammalian counterparts to allow selectable therapeutic action. Parasite protein kinase A (PfPKA) is highly expressed late in the cell cycle of the parasite blood stage and has been shown to phosphorylate a critical invasion protein, Apical Membrane Antigen 1. This enzyme could therefore be a valuable drug target so we have repurposed a substituted 4-cyano-3-methylisoquinoline that has been shown to inhibit rat PKA with the goal of targeting PfPKA. We synthesised a novel series of compounds and, although many potently inhibit the growth of chloroquine sensitive and resistant strains of P. falciparum, they were found to have minimal activity against PfPKA, indicating that they likely have another target important to parasite cytokinesis and invasion.
Department of Chemistry and Physics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria 3086, Australia. b.abbott@latrobe.edu.au.
Melissa J
MJ
Buskes
Centre for Biomedical Research, Burnet Institute, Melbourne, Victoria 3004, Australia and Department of Microbiology and Immunology, Peter Doherty Institute, University of Melbourne, Melbourne, Victoria 3010, Australia.
Katherine L
KL
Harvey
Department of Chemistry and Physics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria 3086, Australia. b.abbott@latrobe.edu.au.
Benjamin J
BJ
Richards
Department of Chemistry and Physics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria 3086, Australia. b.abbott@latrobe.edu.au.
Robabeh
R
Kalhor
Department of Chemistry and Physics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria 3086, Australia. b.abbott@latrobe.edu.au.
Rebecca M
RM
Christoff
Department of Chemistry and Physics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria 3086, Australia. b.abbott@latrobe.edu.au.
Chamodi K
CK
Gardhi
Monash University, Melbourne, Victoria 3800, Australia.
Dene R
DR
Littler
Centre for Biomedical Research, Burnet Institute, Melbourne, Victoria 3004, Australia.
Elliott D
ED
Cope
Centre for Biomedical Research, Burnet Institute, Melbourne, Victoria 3004, Australia.
Boris
B
Prinz
Centre for Biomedical Research, Burnet Institute, Melbourne, Victoria 3004, Australia.
Greta E
GE
Weiss
Department of Chemistry and Physics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria 3086, Australia. b.abbott@latrobe.edu.au.
Nathan J
NJ
O'Brien
Centre for Biomedical Research, Burnet Institute, Melbourne, Victoria 3004, Australia and Department of Microbiology and Immunology, Peter Doherty Institute, University of Melbourne, Melbourne, Victoria 3010, Australia and Monash University, Melbourne, Victoria 3800, Australia.
Brendan S
BS
Crabb
Department of Chemistry and Physics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria 3086, Australia. b.abbott@latrobe.edu.au.
Leslie W
LW
Deady
Centre for Biomedical Research, Burnet Institute, Melbourne, Victoria 3004, Australia and 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. b.abbott@latrobe.edu.au.
Belinda M
BM
Abbott
D000595:Amino Acid Sequence; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D060326:Chemistry Techniques, Synthetic; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development
C511972:4-cyano-3-methylisoquinoline; D000962:Antimalarials; D007546:Isoquinolines; D017868:Cyclic AMP-Dependent Protein Kinases