Alkynamide phthalazinones as a new class of TbrPDEB1 inhibitors

Erik de Heuvel, Abhimanyu K. Singh, Ewald Edink, Tiffany van der Meer, Melanie van der Woude, Payman Sadek, Mikkel P. Krell-Jørgensen, Toine van den Bergh, Johan Veerman, Guy Caljon, Titilola D. Kalejaiye, Maikel Wijtmans, Louis Maes, Harry P. de Koning, Geert Jan Sterk, Marco Siderius, Iwan J.P. de Esch, David G. Brown, Rob Leurs*

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review


Several 3′,5′-cyclic nucleotide phosphodiesterases (PDEs) have been validated as good drug targets for a large variety of diseases. Trypanosoma brucei PDEB1 (TbrPDEB1) has been designated as a promising drug target for the treatment of human African trypanosomiasis. Recently, the first class of selective nanomolar TbrPDEB1 inhibitors was obtained by targeting the parasite specific P-pocket. However, these biphenyl-substituted tetrahydrophthalazinone-based inhibitors did not show potent cellular activity against Trypanosoma brucei (T. brucei) parasites, leaving room for further optimization. Herein, we report the discovery of a new class of potent TbrPDEB1 inhibitors that display improved activities against T. brucei parasites. Exploring different linkers between the reported tetrahydrophthalazinone core scaffold and the amide tail group resulted in the discovery of alkynamide phthalazinones as new TbrPDEB1 inhibitors, which exhibit submicromolar activities versus T. brucei parasites and no cytotoxicity to human MRC-5 cells. Elucidation of the crystal structure of alkynamide 8b (NPD-048) bound to the catalytic domain of TbrPDEB1 shows a bidentate interaction with the key-residue Gln874 and good directionality towards the P-pocket. Incubation of trypanosomes with alkynamide 8b results in an increase of intracellular cAMP, validating a PDE-mediated effect in vitro and providing a new interesting compound series for further studies towards selective TbrPDEB1 inhibitors with potent phenotypic activity.

Original languageEnglish
Pages (from-to)3998-4012
Number of pages15
JournalBioorganic and Medicinal Chemistry
Issue number18
Early online date18 Jun 2019
Publication statusPublished - 15 Sept 2019


  • Crystal structure
  • Human African trypanosomiasis
  • Neglected tropical disease
  • Structure-based drug discovery
  • Tetrahydrophthalazinone
  • Trypanosoma brucei phosphodiesterase B1


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