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

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:24

Article

Amata, Emanuele¹  Bland, Nicholas D.²  Hoyt, Charles T.¹  Settimo, Luca¹  Campbell, Robert K.²  Pollastri, Michael P.¹ 

[1] Northeastern Univ, Dept Chem & Chem Biol, Boston, MA 02115 USA

[2] Marine Biol Lab, Josephine Bay Paul Ctr Comparat Mol Biol & Evolut, Woods Hole, MA 02543 USA

关键词: Antiprotozoal agents;    Cilomilast;    Phosphodiesterase inhibitors;    TbrPDEB1 Trypanosoma brucei;   

DOI  :  10.1016/j.bmcl.2014.07.063

来源: Elsevier

【 摘 要 】

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.

【 授权许可】

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