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Alkynamide phthalazinones as a new class of TbrPDEB1 inhibitors

de Heuvel, Erik, Singh, Abhimanyu K., Edink, Ewald, van der Meer, Tiffany, van der Woude, Melanie, Sadek, Payman, Krell-Jørgensen, Mikkel P., van den Bergh, Toine, Veerman, Johan, Caljon, Guy, and others. (2019) Alkynamide phthalazinones as a new class of TbrPDEB1 inhibitors. Bioorganic & Medicinal Chemistry, . ISSN 0968-0896. (doi:10.1016/j.bmc.2019.06.027) (Access to this publication is currently restricted. You may be able to access a copy if URLs are provided) (KAR id:75603)

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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.

Item Type: Article
DOI/Identification number: 10.1016/j.bmc.2019.06.027
Uncontrolled keywords: Neglected tropical diseaseHuman, African trypanosomiasis, Trypanosoma, brucei phosphodiesterase, B1Structure-based drug, discovery Tetrahydrophthalazinone, Crystal structure
Divisions: Faculties > Sciences > School of Biosciences
Depositing User: Sue Davies
Date Deposited: 29 Jul 2019 14:51 UTC
Last Modified: 19 Aug 2019 08:14 UTC
Resource URI: (The current URI for this page, for reference purposes)
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