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Alkynamide phthalazinones as a new class of TbrPDEB1 inhibitors (Part 2)

DOI: 10.1016/j.bmc.2019.06.026 DOI Help

Authors: Erik De Heuvel (Vrije Universiteit Amsterdam) , Abhimanyu K. Singh (University of Kent) , Pierre Boronat (Vrije Universiteit Amsterdam) , Albert J. Kooistra (Vrije Universiteit Amsterdam) , Tiffany Van Der Meer (Vrije Universiteit Amsterdam) , Payman Sadek (Vrije Universiteit Amsterdam) , Antoni R. Blaazer (Vrije Universiteit Amsterdam) , Nathan C. Shaner (University of California) , Daphne S. Bindels (Scintillon Institute) , Guy Caljon (University of Antwerp) , Louis Maes (University of Antwerp) , Geert Jan Sterk (Vrije Universiteit Amsterdam) , Marco Siderius (Vrije Universiteit Amsterdam) , Michael Oberholzer (Scintillon Institute) , Iwan J. P. De Esch (Vrije Universiteit Amsterdam) , David G. 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: July 2019
Diamond Proposal Number(s): 13689 , 16207

Open Access Open Access

Abstract: Inhibitors against Trypanosoma brucei phosphodiesterase B1 (TbrPDEB1) and B2 (TbrPDEB2) have gained interest as new treatments for human African trypanosomiasis. The recently reported alkynamide tetrahydrophthalazinones, which show submicromolar activities against TbrPDEB1 and anti-T. brucei activity, have been used as starting point for the discovery of new TbrPDEB1 inhibitors. Structure-based design indicated that the alkynamide-nitrogen atom can be readily decorated, leading to the discovery of 37, a potent TbrPDEB1 inhibitor with submicromolar activities against T. brucei parasites. Furthermore, 37 is more potent against TbrPDEB1 than hPDE4 and shows no cytotoxicity on human MRC-5 cells. The crystal structures of the catalytic domain of TbrPDEB1 co-crystalized with several different alkynamides show a bidentate interaction with key-residue Gln874, but no interaction with the parasite-specific P-pocket, despite being (uniquely) a more potent inhibitor for the parasite PDE. Incubation of blood stream form trypanosomes by 37 increases intracellular cAMP levels and results in the distortion of the cell cycle and cell death, validating phosphodiesterase inhibition as mode of action.

Journal Keywords: Trypanosoma brucei phosphodiesterase B1; Enzyme inhibitors; Neglected tropical disease; Human African trypanosomiasis; Structure-based drug discovery; Fluorescence Microscopy

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength)

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