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PreprintRepurposing human PDE4 inhibitors for neglected tropical diseases : design, synthesis and evaluation of cilomilast analogues as Trypanosoma brucei PDEB1 inhibitors( 2014-07) Amata, Emanuele ; Bland, Nicholas D. ; Hoyt, Charles T. ; Settimo, Luca ; Campbell, Robert K. ; Pollastri, Michael P.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.
PreprintEvaluation of pyrrolidine and pyrazolone derivatives as inhibitors of trypanosomal phosphodiesterase B1 (TbrPDEB1)( 2015-04-13) Amata, Emanuele ; Bland, Nicholas D. ; Campbell, Robert K. ; Pollastri, Michael P.Human African trypanosomiasis (HAT) is a parasitic disease, caused by the protozoan pathogen Trypanosoma brucei, which affects thousands every year and which is in need of new therapeutics. Herein we report the synthesis and assessment of a series of pyrrolidine and pyrazolone derivatives of human phosphodiesterase 4 (hPDE4) inhibitors for the assessment of their activity against the trypanosomal phosphodiesterase TbrPDEB1. The synthesized compounds showed weak potency against TbrPDEB1.