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

  • Bioorg Med Chem Lett. 2014 Sep 1;24(17):4084-9. doi: 10.1016/j.bmcl.2014.07.063.
Emanuele Amata  1 ,  Nicholas D Bland  2 ,  Charles T Hoyt  1 ,  Luca Settimo  1 ,  Robert K Campbell  2 ,  Michael P Pollastri  1
Affiliations
  • 1. Northeastern University, Department of Chemistry and Chemical Biology, 417 Egan Research Center, 360 Huntington Avenue, Boston, MA 02115, USA.
  • 2. Marine Biological Laboratory, Josephine Bay Paul Center for Comparative Molecular Biology and Evolution, 7 MBL Street, Woods Hole, MA 02543, USA.
PMID: 25127163 DOI: 10.1016/j.bmcl.2014.07.063
Abstract

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.

Keywords
Antiprotozoal agents; Cilomilast; Phosphodiesterase inhibitors; TbrPDEB1 Trypanosoma brucei.
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