4.5 Article

Repurposing human PDE4 inhibitors for neglected tropical diseases: Design, synthesis and evaluation of cilomilast analogues as Trypanosoma brucei PDEB1 inhibitors

Journal

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 24, Issue 17, Pages 4084-4089

Publisher

PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2014.07.063

Keywords

Antiprotozoal agents; Cilomilast; Phosphodiesterase inhibitors; TbrPDEB1 Trypanosoma brucei

Funding

  1. National Institutes of Health [R01AI082577]

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A medicinal chemistry exploration of the human phosphodiesterase 4 (hPDE4) inhibitor cilomilast (1) was undertaken in order to identify inhibitors of phosphodiesterase B1 of Trypanosoma brucei (TbrPDEB1). T. brucei is the parasite which causes African sleeping sickness, a neglected tropical disease that affects thousands each year, and TbrPDEB1 has been shown to be an essential target of therapeutic relevance. Noting that 1 is a weak inhibitor of TbrPDEB1, we report the design and synthesis of analogs of this compound, culminating in 12b, a sub-micromolar inhibitor of TbrPDEB1 that shows modest inhibition of T. brucei proliferation. (C) 2014 Elsevier Ltd. All rights reserved.

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