Journal
CHEMICAL BIOLOGY & DRUG DESIGN
Volume 85, Issue 5, Pages 549-564Publisher
WILEY
DOI: 10.1111/cbdd.12443
Keywords
GSK-256066; phosphodiesterase inhibitors; TbrPDEB1; TbrPDEB2; Trypanosoma brucei
Funding
- National Institutes of Health [R01AI082577]
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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.
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