Antimalarial activity of novel 4-cyano-3-methylisoquinoline inhibitors against Plasmodium falciparum: design, synthesis and biological evaluation
| Autor: | Leslie W. Deady, Nathan J. O'Brien, Elliott D. Cope, Brendan S. Crabb, Belinda M. Abbott, Chamodi K. Gardhi, Greta E. Weiss, Melissa J. Buskes, Rebecca M. Christoff, Robabeh Kalhor, Paul R. Gilson, Boris Prinz, Dene R. Littler, Benjamin J. Richards, Katherine L. Harvey |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Plasmodium falciparum Drug Evaluation Preclinical Chemistry Techniques Synthetic Biochemistry Antimalarials 03 medical and health sciences Chloroquine medicine Amino Acid Sequence Physical and Theoretical Chemistry Apical membrane antigen 1 biology Drug discovery Kinase Organic Chemistry Cell cycle Isoquinolines biology.organism_classification Cyclic AMP-Dependent Protein Kinases Cell biology 030104 developmental biology Drug Design Cytokinesis Intracellular medicine.drug |
| Zdroj: | Organic & Biomolecular Chemistry. 14:4617-4639 |
| ISSN: | 1477-0539 1477-0520 |
| DOI: | 10.1039/c5ob02517f |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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