Publications & Reports

Antimalarial activity of novel 4-cyano-3-methylisoquinoline inhibitors against Plasmodium falciparum: design, synthesis and biological evaluation.

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
Department of Chemistry and Physics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria 3086, Australia. [email protected]

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.

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 and Monash Micro Imaging.

Publication

  • Journal: Organic & Biomolecular Chemistry
  • Published: 22/04/2016
  • Volume: 14
  • Issue: 20
  • Pagination: 4617-4639

Authors

Health Issue