Catechol pyrazolinones as trypanocidals: fragment-based design, synthesis, and pharmacological evaluation of nanomolar inhibitors of trypanosomal phosphodiesterase B1

J Med Chem. 2012 Oct 25;55(20):8745-56. doi: 10.1021/jm301059b.

Kristina M Orrling ¹, Chimed Jansen, Xuan Lan Vu, Vreni Balmer, Patrick Bregy, Anitha Shanmugham, Paul England, David Bailey, Paul Cos, Louis Maes, Emily Adams, Erika van den Bogaart, Eric Chatelain, Jean-Robert Ioset, Andrea van de Stolpe, Stèphanie Zorg, Johan Veerman, Thomas Seebeck, Geert Jan Sterk, Iwan J P de Esch, Rob Leurs

Affiliations

Affiliation

1 Leiden/Amsterdam Centre of Drug Research-LACDR, Amsterdam Institute of Molecules, Medicines and Systems- AIMMS, Division of Medicinal Chemistry, VU University Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.

PMID: 22963052 DOI: 10.1021/jm301059b

Abstract

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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