Abstract
Parasitic diseases, such as African sleeping sickness, have a significant impact on the health and well-being in the poorest regions of the world. Pragmatic drug discovery efforts are needed to find new therapeutic agents. In this report we describe target repurposing efforts focused on trypanosomal phosphodiesterases. We outline the synthesis and biological evaluation of analogs of sildenafil (1), a human PDE5 inhibitor, for activities against trypanosomal PDEB1 (TbrPDEB1). We find that, while low potency analogs can be prepared, this chemical class is a sub-optimal starting point for further development of TbrPDE inhibitors.
Keywords
neglected disease, Trypanosoma brucei, target repurposing, phosphodiesterase inhibitors, TbrPDEB1, PDE5, sildenafil
Subject Categories
Parasitic diseases - Treatment, Sildenafil, Phosphodiesterases - Inhibitors
Disciplines
Parasitic Diseases | Pharmaceutics and Drug Design
Publisher
Elsevier Ltd.
Publication Date
2-9-2012
Rights Information
Copyright 2012
Rights Holder
Elsevier Ltd.
Recommended Citation
Wang, Cuihua; Ashton, Trent D.; Gustafson, Alden; Bland, Nicholas D.; Ochiana, Stefan O.; Campbell, Robert K.; and Pollastri, Michael P., "Synthesis and evaluation of human phosphodiesterases (PDE) 5 inhibitor analogs as trypanosomal PDE inhibitors. 1. Sildenafil analogs" (2012). Chemistry and Chemical Biology Faculty Publications. Paper 5.
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Notes
NOTICE: this is the author’s version of a work that was accepted for publication in Bioorganic & Medicinal Chemistry Letters. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. The definitive version was published in Bioorganic & Medicinal Chemistry Letters (2012), DOI:10.1016/j.bmcl.2012.01.119.