Abstract
Cyclic nucleotide phosphodiesterases (PDEs) have been identified as important enzyme targets for drug development in both humans and Trypanosoma brucei, the causative agent of human African trypanosomiasis. With this in mind, we recently reported the profiling of a range of human phosphodiesterase inhibitors, showing that human PDE4 inhibitors tend to display the best potency against the trypanosomal phosphodiesterase TbrPDEB1. Among these was GSK-256066, a potent inhibitor of human PDE4 and a weak inhibitor of TbrPDEB1. In this report, we describe the results of a structure-activity relationship study of this chemotype, leading to the discovery of analogs with improved potency against TbrPDEB1 and micromolar inhibition of T. brucei cellular growth. We rationalize the potency trends via molecular docking of the new inhibitors into a recently reported apo structure of TbrPDEB1. The studies in this article will inform future efforts in repurposing human PDE inhibitors as antitrypanosomal agents.
Keywords:
GSK-256066; TbrPDEB1; TbrPDEB2; Trypanosoma brucei; phosphodiesterase inhibitors.
© 2014 John Wiley & Sons A/S.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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3',5'-Cyclic-AMP Phosphodiesterases / antagonists & inhibitors*
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3',5'-Cyclic-AMP Phosphodiesterases / metabolism
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Aminoquinolines / chemistry
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Aminoquinolines / pharmacology
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Aminoquinolines / therapeutic use
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Binding Sites
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Cyclic Nucleotide Phosphodiesterases, Type 4 / chemistry
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Cyclic Nucleotide Phosphodiesterases, Type 4 / metabolism
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Drug Repositioning
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Humans
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Molecular Docking Simulation
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Neglected Diseases / drug therapy
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Phosphodiesterase 4 Inhibitors / chemistry
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Phosphodiesterase 4 Inhibitors / pharmacology
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Phosphodiesterase 4 Inhibitors / therapeutic use
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Protein Structure, Tertiary
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Protozoan Proteins / antagonists & inhibitors*
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Protozoan Proteins / metabolism
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Quinolines / chemistry
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Quinolines / metabolism
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Quinolines / pharmacology
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Structure-Activity Relationship
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Sulfones / chemistry
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Sulfones / pharmacology
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Sulfones / therapeutic use
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Trypanosoma brucei brucei / drug effects
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Trypanosoma brucei brucei / enzymology
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Trypanosomiasis, African / drug therapy
Substances
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6-((3-((dimethylamino)carbonyl)phenyl)sulfonyl)-8-methyl-4-((3-methyloxyphenyl)amino)-3-quinolinecarboxamide
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Aminoquinolines
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Phosphodiesterase 4 Inhibitors
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Protozoan Proteins
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Quinolines
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Sulfones
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quinoline
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3',5'-Cyclic-AMP Phosphodiesterases
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Cyclic Nucleotide Phosphodiesterases, Type 4
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PDEB1 protein, Trypanosoma brucei