2. Academic Validation
  3. Alkynamide phthalazinones as a new class of TbrPDEB1 inhibitors

Alkynamide phthalazinones as a new class of TbrPDEB1 inhibitors

  • Bioorg Med Chem. 2019 Sep 15;27(18):3998-4012. doi: 10.1016/j.bmc.2019.06.027.
Erik de Heuvel 1,  Abhimanyu K Singh 2,  Ewald Edink 1,  Tiffany van der Meer 1,  Melanie van der Woude 1,  Payman Sadek 1,  Mikkel P Krell-Jørgensen 1,  Toine van den Bergh 3,  Johan Veerman 3,  Guy Caljon 4,  Titilola D Kalejaiye 5,  Maikel Wijtmans 1,  Louis Maes 4,  Harry P de Koning 5,  Geert Jan Sterk 1,  Marco Siderius 1,  Iwan J P de Esch 1,  David G Brown 2,  Rob Leurs 6
Affiliations

Affiliations

  • 1 Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems, Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands.
  • 2 School of Biosciences, University of Kent, Canterbury CT2 7NJ, UK.
  • 3 Mercachem, Kerkenbos 1013, 6546 BB Nijmegen, The Netherlands.
  • 4 Laboratory for Microbiology, Parasitology and Hygiene, Universiteitsplein 1, University of Antwerp, 2610 Wilrijk, Belgium.
  • 5 Institute of Infection, Immunity and Inflammation, University of Glasgow, 120 University Place, Glasgow G12 8TA, UK.
  • 6 Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems, Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands. Electronic address: r.leurs@vu.nl.
PMID: 31327675 DOI: 10.1016/j.bmc.2019.06.027
Abstract

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.

Keywords

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

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