Antimalarial activity of novel 4-cyano-3-methylisoquinoline inhibitors against Plasmodium falciparum: design, synthesis and biological evaluation. Issue 20 (22nd April 2016)

• Record Type: Journal Article
• Authors: 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.
• Is Part Of: Organic & biomolecular chemistry. Volume 14:Issue 20(2016)
• Page Start: 4617
• Page End: 4639
• Publication Date: 2016-04-22
• Subjects: Chemistry, Organic -- Periodicals; Bioorganic chemistry -- Periodicals; Chemistry, Physical organic -- Periodicals; 547
• DOI: 10.1039/c5ob02517f
• Languages: English
• ISSNs: 1477-0520

Abstract

Abstract : A series of 4-cyano-3-methylisoquinolines have been shown to inhibit parasite cytokinesis and erythrocyte invasion. 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 ( Pf PKA) 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 Pf PKA. 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 Pf PKA, indicating that they likely have another target important to parasite cytokinesis and invasion.