Publication

Article Metrics

Citations


Online attention

Alkynamide phthalazinones as a new class of TbrPDEB1 inhibitors

DOI: 10.1016/j.bmc.2019.06.027 DOI Help

Authors: Erik De Heuvel (Vrije Universiteit Amsterdam) , Abhimanyu K. Singh (University of Kent) , Ewald Edink (Vrije Universiteit Amsterdam) , Tiffany Van Der Meer (Vrije Universiteit Amsterdam) , Melanie Van Der Woude (Vrije Universiteit Amsterdam) , Payman Sadek (Vrije Universiteit Amsterdam) , Mikkel P. Krell-jørgensen (Vrije Universiteit Amsterdam) , Toine Van Den Bergh (Mercachem) , Johan Veerman (Mercachem) , Guy Caljon (University of Antwerp) , Titilola D. Kalejaiye (University of Glasgow) , Maikel Wijtmans (Vrije Universiteit Amsterdam) , Louis Maes (University of Antwerp) , Harry P. De Koning (University of Glasgow) , Geert Jan Sterk (Vrije Universiteit Amsterdam) , Marco Siderius (Vrije Universiteit Amsterdam) , Iwan J. P. De Esch (Vrije Universiteit Amsterdam) , David Brown (University of Kent) , Rob Leurs (Vrije Universiteit Amsterdam)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Bioorganic & Medicinal Chemistry

State: Published (Approved)
Published: June 2019
Diamond Proposal Number(s): 13689

Open Access Open Access

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.

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

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography