Antimalarial activity of novel 4-cyano-3-methylisoquinoline inhibitors against Plasmodium falciparum

Design, synthesis and biological evaluation

Melissa J. Buskes, Katherine L. Harvey, Benjamin J. Richards, Robabeh Kalhor, Rebecca M. Christoff, Chamodi K. Gardhi, Dene R. Littler, Elliott D. Cope, Boris Prinz, Greta E. Weiss, Nathan J. O'Brien, Brendan S. Crabb, Leslie W. Deady, Paul R. Gilson, Belinda M. Abbott

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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.
Original languageEnglish
Pages (from-to)4617-4639
Number of pages23
JournalOrganic and Biomolecular Chemistry
Volume14
Issue number20
DOIs
Publication statusPublished - 22 Apr 2016

Cite this

Buskes, Melissa J. ; Harvey, Katherine L. ; Richards, Benjamin J. ; Kalhor, Robabeh ; Christoff, Rebecca M. ; Gardhi, Chamodi K. ; Littler, Dene R. ; Cope, Elliott D. ; Prinz, Boris ; Weiss, Greta E. ; O'Brien, Nathan J. ; Crabb, Brendan S. ; Deady, Leslie W. ; Gilson, Paul R. ; Abbott, Belinda M. / Antimalarial activity of novel 4-cyano-3-methylisoquinoline inhibitors against Plasmodium falciparum : Design, synthesis and biological evaluation. In: Organic and Biomolecular Chemistry. 2016 ; Vol. 14, No. 20. pp. 4617-4639.
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title = "Antimalarial activity of novel 4-cyano-3-methylisoquinoline inhibitors against Plasmodium falciparum: Design, synthesis and biological evaluation",
abstract = "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.",
author = "Buskes, {Melissa J.} and Harvey, {Katherine L.} and Richards, {Benjamin J.} and Robabeh Kalhor and Christoff, {Rebecca M.} and Gardhi, {Chamodi K.} and Littler, {Dene R.} and Cope, {Elliott D.} and Boris Prinz and Weiss, {Greta E.} and O'Brien, {Nathan J.} and Crabb, {Brendan S.} and Deady, {Leslie W.} and Gilson, {Paul R.} and Abbott, {Belinda M.}",
year = "2016",
month = "4",
day = "22",
doi = "10.1039/c5ob02517f",
language = "English",
volume = "14",
pages = "4617--4639",
journal = "Organic and Biomolecular Chemistry",
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Buskes, MJ, Harvey, KL, Richards, BJ, Kalhor, R, Christoff, RM, Gardhi, CK, Littler, DR, Cope, ED, Prinz, B, Weiss, GE, O'Brien, NJ, Crabb, BS, Deady, LW, Gilson, PR & Abbott, BM 2016, 'Antimalarial activity of novel 4-cyano-3-methylisoquinoline inhibitors against Plasmodium falciparum: Design, synthesis and biological evaluation', Organic and Biomolecular Chemistry, vol. 14, no. 20, pp. 4617-4639. https://doi.org/10.1039/c5ob02517f

Antimalarial activity of novel 4-cyano-3-methylisoquinoline inhibitors against Plasmodium falciparum : Design, synthesis and biological evaluation. / Buskes, Melissa J.; Harvey, Katherine L.; Richards, Benjamin J.; Kalhor, Robabeh; Christoff, Rebecca M.; Gardhi, Chamodi K.; Littler, Dene R.; Cope, Elliott D.; Prinz, Boris; Weiss, Greta E.; O'Brien, Nathan J.; Crabb, Brendan S.; Deady, Leslie W.; Gilson, Paul R.; Abbott, Belinda M.

In: Organic and Biomolecular Chemistry, Vol. 14, No. 20, 22.04.2016, p. 4617-4639.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Antimalarial activity of novel 4-cyano-3-methylisoquinoline inhibitors against Plasmodium falciparum

T2 - Design, synthesis and biological evaluation

AU - Buskes, Melissa J.

AU - Harvey, Katherine L.

AU - Richards, Benjamin J.

AU - Kalhor, Robabeh

AU - Christoff, Rebecca M.

AU - Gardhi, Chamodi K.

AU - Littler, Dene R.

AU - Cope, Elliott D.

AU - Prinz, Boris

AU - Weiss, Greta E.

AU - O'Brien, Nathan J.

AU - Crabb, Brendan S.

AU - Deady, Leslie W.

AU - Gilson, Paul R.

AU - Abbott, Belinda M.

PY - 2016/4/22

Y1 - 2016/4/22

N2 - 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.

AB - 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.

UR - http://www.ncbi.nlm.nih.gov/pubmed/27105169

U2 - 10.1039/c5ob02517f

DO - 10.1039/c5ob02517f

M3 - Article

VL - 14

SP - 4617

EP - 4639

JO - Organic and Biomolecular Chemistry

JF - Organic and Biomolecular Chemistry

SN - 1477-0520

IS - 20

ER -