Journal of Medicinal Chemistry p. 8745 - 8756 (2012)
Update date:2022-07-29
Topics:
Orrling, Kristina M.
Jansen, Chimed
Vu, Xuan Lan
Balmer, Vreni
Bregy, Patrick
Shanmugham, Anitha
England, Paul
Bailey, David
Cos, Paul
Maes, Louis
Adams, Emily
Van Den Bogaart, Erika
Chatelain, Eric
Ioset, Jean-Robert
Van De Stolpe, Andrea
Zorg, Stèphanie
Veerman, Johan
Seebeck, Thomas
Sterk, Geert Jan
De Esch, Iwan J. P.
Leurs, Rob
Trypanosomal phosphodiesterases B1 and B2 (TbrPDEB1 and TbrPDEB2) play an important role in the life cycle of Trypanosoma brucei, the causative parasite of human African trypanosomiasis (HAT), also known as African sleeping sickness. We used homology modeling and docking studies to guide fragment growing into the parasite-specific P-pocket in the enzyme binding site. The resulting catechol pyrazolinones act as potent TbrPDEB1 inhibitors with IC50 values down to 49 nM. The compounds also block parasite proliferation (e.g., VUF13525 (20b): T. brucei rhodesiense IC50 = 60 nM, T. brucei brucei IC50 = 520 nM, T. cruzi = 7.6 μM), inducing a typical multiple nuclei and kinetoplast phenotype without being generally cytotoxic. The mode of action of 20b was investigated with recombinantly engineered trypanosomes expressing a cAMP-sensitive FRET sensor, confirming a dose-response related increase of intracellular cAMP levels in trypanosomes. Our findings further validate the TbrPDEB family as antitrypanosomal target.
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